Keywords: Corticosterone-releasing hormone, Adrenocorticotropin, Open-field, Hole-Board, Multicompartment Chamber, Elevated Plus-Maze, Elevated T-Maze, Emergence Test, Depensive Withdrawal Test, Light-Dark Box

When injected via the intracerebroventricular route, corticosterone-releasing hormone (CRH) reduced exploration in the elevated plus-maze, the center region of the open-field, and the large chamber in the defensive withdrawal test. The anxiogenic action of CRH in the elevated plus-maze also occurred when infused in basolateral amygdala, ventral hippocampus, lateral septum, bed nucleus of the stria terminalis, nucleus accumbens, periaqueductal grey, and medial frontal cortex. The anxiogenic action of CRH in the defensive withdrawal test was reproduced when injected in the locus coeruleus, while the amygdala, hippocampus, lateral septum, nucleus accumbens, and lateral globus pallidus contribute to center zone exploration in the open-field. In addition to elevated plus-maze and open-field tests, the amygdala appears as a target region for CRH-mediated anxiety in the elevated Tmaze. Thus, the amygdala is the principal brain region identified with these three tests and further research must identify the neural circuits underlying this form of anxiety.

Mont-Saint-Aignan Cedex France, TEL +33 02 35 14 61 08, FAX +33 02 35 14 63 49, Email: robert.lalonde@univ-rouen.fr 2 Université de Lorraine, Laboratoire "Stress, Immunité, Pathogènes" EA 7300 and Service de Microscopie Electronique, Faculté de Médecine, 9 avenue de la Forêt de Haye, CHRU de Nancy, 54500 Vandoeuvre-les-Nancy, France

HPA axis and behavior

Figure 1 provides an overall view of anatomical regions subserving the stress response. The paraventricular hypothalamus secretes into hypophysial portal vessels corticosterone-releasing hormone (CRH), a 41 amino acid neuropeptide that promotes the release from the pituitary gland of adrenocorticotropin (ACTH), which in turn releases glucorticoids from the adrenal gland [START_REF] Selye | Forty years of stress research: principal remaining problems and misconceptions[END_REF][START_REF] Vale | Characterization of a 41-residue ovinehypothalamic peptide that stimulates secretion of corticotropin and betaendorphin[END_REF].

Once in the general circulation, glucocorticoids exert feedback inhibition on hypothalamic CRH and hypophysial ACTH [START_REF] Canny | Glucocorticoids regulate ovine hypophysial portal levels of corticotropin-releasing factor and arginine vasopressin in a stress-specific manner[END_REF][START_REF] Keller-Wood | Corticosteroid inhibition of ACTH secretion[END_REF]. CRH may also exert positive feedback control on paraventricular CRH neurons via CRH receptor-1 (CRHR1) [START_REF] Mansi | Regulation of corticotropin-releasing factor type 1 (CRF1) receptor messenger ribonucleic acid in the paraventricular nucleus of rat hypothalamus by exogenous CRF[END_REF]. In addition to the paraventricular hypothalamus, CRH-containing neurons are found in the bed nucleus of the stria terminalis [START_REF] Merchenthaler | Immunocytochemical localization of corticotropin-releasing factor (CRF) in the rat brain[END_REF][START_REF] Phelix | Demonstration of distinct corticotropin releasing factor-containing neuron populations in the bed nucleus of the stria terminalis. A light and electron microscopic immunocytochemical study in the rat[END_REF], which projects to the paraventricular hypothalamus [START_REF] Champagne | CRFergic innervation of the paraventricular nucleus of the rat hypothalamus: a tract-tracing study[END_REF] and the dorsal vagal complex (Gray and Magnuson, 1987). CRH-containing neurons in the bed nucleus of the stria terminalis and central amygdala communicate with a wide range of forebrain structures (Gray, 1993;[START_REF] Heinrichs | Corticotropin-releasing factor in brain: a role in activation, arousal, and affect regulation[END_REF][START_REF] Swanson | Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study[END_REF].

CRH, glucocorticoid, and mineralocorticoid receptors

CRH binds to two receptors: CRHR1 and CRHR2 [START_REF] Hashimoto | Physiological roles of corticotropin-releasing hormone receptor type 2[END_REF][START_REF] Hauger | Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets[END_REF][START_REF] Keenan | Biased signalling from the glucocorticoid receptor: renewed opportunity for tailoring glucocorticoid activity[END_REF][START_REF] Orozco-Cabal | Regulation of synaptic transmission by CRF receptors[END_REF][START_REF] Steckler | Corticotopin-releasing hormone receptor subtypes and emotion[END_REF][START_REF] Vaughan | Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor[END_REF], preferentially to CRHR1, while urocortin-1 binds preferentially to CRHR2 [START_REF] Bittencourt | Urocortin expression in rat brain: evidence against a pervasive relationship of urocortin-containing projections with targets bearing type 2 CRF receptors[END_REF][START_REF] Vaughan | Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor[END_REF]. In one preparation rich in CRHR2, CRH was 30-fold less potent than urocortin-1, urotensin, and sauvagine (Donaldson et al., 1996) and 100-fold less potent than urocortin-2 [START_REF] Reyes | Urocortin II: a member of the corticotropin releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors[END_REF]. Urocortin-3 is another selective CRHR2 agonist (Venihaki et al., Sanchez, 2014), whereas dexamethasone is a much more selective agonist at the glucocorticoid site [START_REF] Spencer | Corticosterone regulation of type I and type II adrenal steroid receptors in brain, pituitary and immune tissue[END_REF]. Glucocorticoid receptor mapping indicates high immunoreactivity in paraventricular, anterior periventricular, and ventral mediobasal hypothalamus as well as CA1-CA2 subregions of the hippocampal formation, medium to high immunoreactivity throughout neocortex, and medium immunoreactivity in thalamic nuclei and central amygdala [START_REF] Fuxe | Mapping of glucocorticoid receptor immunoreactive neurons in the rat tel-and diencephalon using a monoclonal antibody against rat liver glucocorticoid receptor[END_REF][START_REF] Morimoto | Distribution of glucocorticoid receptor immunoreactivity and mRNA in the rat brain: an immunohistochemical and in situ hybridization study[END_REF]. There is also medium to high immunoreactivity of this receptor on monoaminergic neurons containing dopamine, noradrenaline, and 5hydroxytryptamine (5HT) [START_REF] Härfstrand | Glucocorticoid receptor immunoreactivity in monoaminergic neurons of rat brain[END_REF]. Glucocorticoid receptor expression is also abundant in the nucleus of the solitary tract [START_REF] Herman | Regulation of adrenocorticosteroid receptor mRNA expression in the central nervous system[END_REF]. In addition to neurons, the glucocorticoid receptor is prominent on glial cells [START_REF] Vielkind | Type II glucocorticoid receptors are expressed in oligodendrocytes and astrocytes[END_REF].

Mineralocorticoid receptors are mostly occupied under basal corticosterone levels while glucocorticoid receptors are mostly occupied under stressful conditions or circadian peaks (De Kloet, 1991). Indeed, levels of corticosterone, the main adrenal hormone in rodents commonly measured by fluorescence [START_REF] Zenker | The estimation of small amounts of corticosterone in rat plasma[END_REF] or radioimmunuassay [START_REF] Etches | A radioimmunoassay for corticosterone and its application to the measurement of stress in poultry[END_REF][START_REF] Murphy | Some studies of the protein binding of steroids and their application to the routine micro and ultramicro measurement of various steroids in body fluids by competitive protein binding radioassay[END_REF], fluctuate according to daily rythms [START_REF] Beuving | Daily rhythm of corticosterone in laying hens and the influence of egg laying[END_REF]. The mixed population of glucocorticoid and mineralocorticoid receptors present in the hippocampus differs on electrophysiological grounds. In the CA1 subregion of the hippocampal slice, population spike-long term potentiation (PS-LTP) amplitudes were greater than normal only at low corticosterone concentrations and high calcium medium [START_REF] Rey | Corticosterone effects on long-term potentiation in mouse hippocampal slices[END_REF]. PS-LTP amplitudes increased similarly after applying the mineralocorticoid receptor agonist, aldosterone. At high corticosterone concentrations, PS-LTP amplitudes decreased in either high or low calcium medium, an effect reversed by coapplication with a glucocorticoid receptor antagonist, RU486 (also known as RU38486 or mifepristone, Allen et al., 1988). Still on hippocampal slices, mifepristone decreased population spike amplitudes in mice [START_REF] Rey | Effects of RU 486 on hippocampal slice electrophysiology in normal and adrenalectomized BALB/c mice[END_REF] and adrenalectomized rats, an effect counteracted by corticosterone, in turn suppressed by mifepristone [START_REF] Joëls | Effects of glucocorticoids and norepinephrine on the excitability in the hippocampus[END_REF]. The lower amplitudes after hyperpolarization in adrenalectomized rats were enhanced in aged relative to young rats [START_REF] Kerr | Corticosteroid modulation of hippocampal potentials: increased effect with aging[END_REF]. Unlike most types of habituation, habituation of the HPA axis is paradoxically stronger and quicker after exposure to more severe or longer-lasting stimuli [START_REF] Rabasa | Adaptation of the hypothalamus-pituitary-adrenal axis to daily repeated stress does not follow the rules of habituation: a new perspective[END_REF].

Glucocorticoid effects on neurotransmitters

Glucocorticoids affect neurotransmitters involved in exploratory activity or anxiety, including gamma-amino butyric acid (GABA) and monoamines such as dopamine, noradrenaline, and 5HT originating in brainstem and projecting widely to the limbic system and neocortex [START_REF] Mcewen | The brain as a target for steroid hormone action[END_REF][START_REF] Moore | Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems[END_REF]. In particular, corticosterone blocked GABA reuptake in the hippocampus [START_REF] Miller | Modulation of high affinity GABA uptake into hippocampal synaptosomes by glucocorticoids[END_REF] and facilitated 5HT reuptake and release in the hypothalamus (Cardinali and Gomez, 1977;[START_REF] Vermes | Effects of hypophysectomy, adrenalectomy and corticosterone treatment on uptake and release of putative central neurotransmitters by rat hypothalamic tissue in vitro[END_REF]. In several brain regions, CRH increased concentrations of dihydroxyphenylacetic acid (DOPAC), the main dopamine catabolite, and 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG), the main noradrenaline catabolite [START_REF] Dunn | Corticotropin-releasing factor administration elicits a stress-like activation of cerebral catecholaminergic systems[END_REF]. But in other brain regions, CRH had no effect on dopamine, noradrenaline, and 5HT concentrations. In the hypothalamus, intracerebroventricular (icv)-infused CRH increased levels of dopamine, noradrenaline, and the major 5HT metabolite, 5-hydroxy-indole-acetic acid (5HIAA) [START_REF] Song | Behavioral, neurochemical, and immunological responses to CRF administration: is CRF a mediator of stress?[END_REF]. Likewise, CRH injected in the ventral tegmental area decreased dopamine metabolism in the prefrontal cortex as measured by homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations [START_REF] Kalivas | Neurochemical and behavioral effects of corticotropin-releasing factor in the ventral tegmental area of the rat[END_REF]. Effects on noradrenaline may include the periphery, since dexamethasone and another synthetic glucocorticoid, RU28362, increased beta-adrenergic binding in arterial smooth muscle cells [START_REF] Jazayeri | Glucocorticoid modulation of betaadrenergic receptors of cultured rat arterial smooth muscle cells[END_REF].

Glucocorticoid effects on inflammation

In addition to direct actions on neurotransmitter function, HPA peptides may affect behavior via inflammatory-related processes. In contrast to the antiinflammatory action of glucocorticoids [START_REF] Sapolsky | How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions[END_REF], CRH possesses proinflammatory properties [START_REF] Karalis | Autocrine or paracrine inflammatory actions of corticotropinreleasing hormone in vivo[END_REF], as do the glucocorticoid receptor antagonist, mifepristone [START_REF] Laue | Glucocorticoid antagonists and the role of glucocorticoids at the resting and stress state[END_REF]. In particular, glucocorticoids are involved in inflammation-mediated arthritis. Indeed, arthritic-susceptible Lewis rats were impaired in corticotropin and corticosterone responses to group A streptococcal cell wall pepotidoglycan polysaccharide, whereas arthritic-free Fischer rats were not [START_REF] Sternberg | Inflammatory mediator-induced hypothalamic-pituitaryadrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats[END_REF].

Molecular pathways of CRH effects

Several molecular pathways have been identified regarding CRH-mediated effects [START_REF] Hauger | Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets[END_REF][START_REF] Hauger | Role of CRF receptor signaling in stress vulnerability, anxiety, and depression[END_REF]. In particular, Epac-dependent CRHR1 signaling via the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK-MAPK) pathway potentiates brain-derived neurotrophic factor (BDNF)-stimulated tropomyosin receptor kinase B (TrkB) signaling. CRHR1 may mediate active defensive responses triggered by escapable stressors and CRHR2 anxiety-like responses induced by inescapable, uncontrollable stressors.

Behavioral tests

Although several reviews have appeared since the 1980s concerning HPA hormones and behavior [START_REF] Dunn | Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses?[END_REF][START_REF] Koob | Corticotropin-releasing factor and behavior[END_REF][START_REF] Koob | A role for corticotropin releasing factor and urocortin in behavioral responses to stressors[END_REF][START_REF] Koob | The role of corticotropin-releasing factor in behavioural responses to stress[END_REF][START_REF] Reul | Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression[END_REF][START_REF] Steckler | Corticotopin-releasing hormone receptor subtypes and emotion[END_REF][START_REF] Sterner | Behavioral and neurobiological consequences of prolonged glucocorticoid exposure in rats: relevance to depression[END_REF][START_REF] Tovote | Neuronal circuits for fear and anxiety[END_REF], none provides a global picture on the neuroanatomical basis of exploratory activity in open-field, holeboard, elevated plus-maze, elevated T-maze, defensive withdrawal, and bright-dark box, all at least partially validated tests of anxiety [START_REF] Belzung | Measuring normal and pathological anxiety-like behaviour in mice: a review[END_REF][START_REF] Bourin | Animal models for screening anxiolytic-like drugs: a perspective[END_REF][START_REF] Bourin | The mouse light/dark box test[END_REF][START_REF] Calabrese | An assessment of anxiolytic drug screening tests: hormetic dose responses predominate[END_REF][START_REF] Campos | Animal models of anxiety disorders and stress[END_REF][START_REF] Crawley | Exploratory behavior models of anxiety in mice[END_REF]Dawson and Tricklebank, 1995;[START_REF] Ennaceur | Preclinical animal anxiety research -flaws and prejudices[END_REF][START_REF] File | The rat corticosterone response: habituation and modification by chlordiazepoxide[END_REF][START_REF] File | Factors controlling measures of anxiety and responses to novelty in the mouse[END_REF][START_REF] File | Validity of head-dipping as a measure of exploration in a modified hole-board[END_REF]Graeff et al., 1998;[START_REF] Haller | Classical and novel approaches to the preclinical testing of anxiolytics: a critical evaluation[END_REF][START_REF] Hascoët | The mouse light-dark paradigm: a review[END_REF][START_REF] Hogg | A review of the validity and variability of the elevated plus-maze as an animal model of anxiety[END_REF][START_REF] Kliethermes | Anxiety-like behaviors following chronic ethanol exposure[END_REF][START_REF] Kulkarni | Elevated plus-maze: a novel psychobehavioral tool to measure anxiety in rodents[END_REF][START_REF] Pinheiro | Elevated mazes as animal models of anxiety: effects of serotonergic agents[END_REF][START_REF] Ramos | Animal models of anxiety: do I need multiple tests?[END_REF][START_REF] Rodgers | Anxiety, defence and the elevated plus-maze[END_REF][START_REF] Roth | Stress, behavioral arousal, and open field activity-a reexamination of emotionality in the rat[END_REF][START_REF] Tsang | A systematic review on the anxiolytic effects of aromatherapy on rodents under experimentally induced anxiety models[END_REF][START_REF] Wall | Methodological and conceptual issues in the use of the elevated plus-maze as a psychological measurement instrument of animal anxiety-like behavior[END_REF][START_REF] Walsh | The open-field test: a critical review[END_REF]. Functional interactions exist between open-field, elevated plus-maze, and emergence tests, the latter being an adaptation of defensive withdrawal. Indeed, open-field, elevated plus-maze, and emergence measures were interrelated in C57BL/6J and BALB/c mice either uninjected [START_REF] Lalonde | Relations between open-field, elevated plusmaze, and emergence tests as displayed by C57BL/6J and BALB/c mice[END_REF] or injected with GABA-anxiolytic agents (Lalonde andStrazielle, 2010, 2012). For uninjected mice in the entire sample, ambulation and rears in the open-field were positively correlated with open and enclosed arm visits of the elevated plus-maze. Ambulatory movements, stereotyped movements, and rears in the open-field were negatively correlated with emergence latencies. Significant correlations were also found between emergence latencies and exploration of the elevated plus-maze in chlordiazepoxide-or ethanol-treated mice (Lalonde andStrazielle, 2010, 2012). Likewise, significant correlations were obtained in C57BL/6J and BALB/c mice between open-field and elevated plus-maze measures based on principal component analyses [START_REF] Carola | Evaluation of the elevated plus-maze and open-field tests for the assessment of anxiety-related behaviour in inbred mice[END_REF]. Open-field activity was also correlated with home-cage activity in a population of C57BL/6J, 129X1/SvJ, and 129P3/J mice [START_REF] Tang | Home cage activity and activity-based measures of anxiety in 129P3/J, 129X1/SvJ and C57BL/6J mice[END_REF]. Moreover, time spent in open arms of the elevated plus-maze was positively correlated with time spent in the white compartment of the light-dark box as well as number of head dips in the hole-board by CD1 mice, the latter two variables being also positively intercorrelated [START_REF] Do-Rego | Comparisons between anxiety tests for selection of anxious and non anxious mice[END_REF]. Factor analyses on six inbred rat strains revealed one factor with high loadings for center of the open-field, open arms of the elevated plus-maze, and white compartment of the light/dark box, variables related to approach/avoidance of aversive stimuli [START_REF] Ramos | A multiple-test study of anxiety-related behaviours in six inbred rat strains[END_REF]. On the contrary, open-field and elevated plusmaze measures were not intercorrelated in rats of a single strain [START_REF] Sudakov | Estimation of the level of anxiety in rats: differences in results of open-field test, elevated plus-maze test, and Vogel's conflict test[END_REF].

A physiological convergence between open-field and elevated plus-maze tests was reported with respect to body surface temperatures in domestic mice of wild origin [START_REF] Lecorps | Assessment of anxiety in open field and elevated plus maze using infrared thermography[END_REF]. Initial body temperatures measured by infrared thermography at the start of open-field and elevated plus-maze procedures predicted the levels of exploration in each test. Moreover, rats with high open-field activity were characterized by a greater variability in post-test heart rate relative to those with low activity [START_REF] Kur'yanova | Heart rate variability in nonlinear rats with different orientation and exploratory activity in the open field[END_REF].

In view of inter-test correlations of variable strength, one should expect common effects in regard to CRH, ACTH, and corticosterone. A limiting factor is the interlaboratory variability in some tests of exploratory activity. Despite the use of a standard protocol, differences in elevated plus-maze and open-field data were reported in different laboratories in a population of A/J, BALB/cByJ, C57BL/6J, DBA/2J, 129/Sv-ter, and 129/SvEvTac inbred mouse strains, the F2 hybrid cross of C57BL/6J and DBA/2J, and the Htr1b null mutant lacking the 5HT1B receptor maintained on the 129/Sv-ter background [START_REF] Crabbe | Genetics of mouse behavior: interactions with laboratory environment[END_REF]. In another standard protocol, interlaboratory differences in elevated plus-maze though not open-field data were reported in C57BL/6N mice [START_REF] Lewejohann | Environmental bias? Effects of housing conditions, laboratory environment and experimenter on behavioral tests[END_REF]. Subtle differences in the way experimenters handle mice appear responsible for interlaboratory differences in these two tests [START_REF] Bohlen | Experimenter effects on behavioral test scores of eight inbred mouse strains under the influence of ethanol[END_REF].

Open-field

General activity

The open-field test can be measured under either novel or familar conditions depending on whether the animal had been previously adapted to the apparatus [START_REF] Walsh | The open-field test: a critical review[END_REF]. Exposure to a novel open-field raised plasma corticosterone levels in mature [START_REF] Campbell | Differential regulation of behavioral, genomic, and neuroendocrine responses by CRF infusions in rats[END_REF][START_REF] Marin | Chronic restraint or variable stresses differently affect the behavior, corticosterone secretion and body weight in rats[END_REF] and onemonth-old [START_REF] Suchecki | Pituitary-adrenal axis and behavioural responses of maternally deprived juvenile rats to the open field[END_REF] rats, in the latter group plasma ACTH levels increasing as well. Restraint or variable stress conditions prior to open-field exposure further increased plasma corticosterone levels [START_REF] Marin | Chronic restraint or variable stresses differently affect the behavior, corticosterone secretion and body weight in rats[END_REF]. Plasma corticosterone levels were negatively correlated with open-field activity in control but not pre-stressed rats. Thus, open-field exposure appears as a mildly stressful procedure and rats with the least activity had maximal plasma corticosterone levels.

The corticosterone response to open-field exposure was attenuated in Pacap null mutant mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP, [START_REF] Tsukiyama | PACAP centrally mediates emotional stress-induced corticosterone responses in mice[END_REF], an ACTH releaser [START_REF] Vaudry | Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery[END_REF]. The corticosterone response was not attenuated in these mutants under cold or ether stress, indicating selectivity to the open-field paradigm [START_REF] Tsukiyama | PACAP centrally mediates emotional stress-induced corticosterone responses in mice[END_REF]. In addition, open-field exposure elevated CRHR1 expression in hypothalamus and frontal cortex in rats but decreased it in hippocampus [START_REF] O'malley | Strain differences in stress-induced changes in central CRF1 receptor expression[END_REF]. [START_REF] Kalin | Corticotropinreleasing factor administered intraventricularly to rhesus monkeys[END_REF] first reported on the behavioral effects of CRH, namely huddling and lying down behaviors in monkeys, an anxiogenic-like pattern confirmed by studies in rodents exploring the open-field as first reviewed by [START_REF] Koob | Corticotropin-releasing factor and behavior[END_REF]. Indeed, icv-injected CRH decreased motor activity in a novel open-field (Bakke et al., 1990;[START_REF] Campbell | Differential regulation of behavioral, genomic, and neuroendocrine responses by CRF infusions in rats[END_REF][START_REF] Koob | Stimulant and anxiogenic effects of corticotropin releasing factor[END_REF][START_REF] Sutton | Corticotropin releasing factor produces behavioural activation in rats[END_REF][START_REF] Venihaki | Urocortin III, a brain neuropeptide of the corticotropin-releasing hormone family: modulation by stress and attenuation of some anxiety-like behaviours[END_REF]. This result appears selective for CRH in that icv injections of neuromedin S, another activator of the HPA system, had no effect in a novel open-field [START_REF] Jaszberenyi | Endocrine and behavioral effects of neuromedin S[END_REF]. In one study [START_REF] Song | Behavioral, neurochemical, and immunological responses to CRF administration: is CRF a mediator of stress?[END_REF], icvinjected CRH increased activity in a novel open-field, but this effect was seen after four daily injections. Usually, icv-injected CRH increases motor activity in a familiar open-field [START_REF] Butler | Corticotropinreleasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus[END_REF][START_REF] Jones | The behavioural effects of corticotropin-releasing factor-related peptides in rats[END_REF][START_REF] Koob | Stimulant and anxiogenic effects of corticotropin releasing factor[END_REF][START_REF] Menzaghi | Characterization of a novel and potent corticotropin-releasing factor antagonist in rats[END_REF][START_REF] Spina | Appetite suppressant effects of urocortin, a CRF-related neuropeptide[END_REF][START_REF] Spina | Behavioral effects of central administration of the novel CRF antagonist astressin in rats[END_REF][START_REF] Sutton | Corticotropin releasing factor produces behavioural activation in rats[END_REF][START_REF] Zorrilla | Effects of antalarmin, a CRF type 1 receptor antagonist, on anxiety-like behavior and motor activation in the rat[END_REF], consistent with increased arousal. The activational effect in a familiar openfield is independent of corticosterone, since it was found in hypophysectomized rats [START_REF] Eaves | Effects of corticotropin releasing factor on locomotor activity in hypophysectomized rats[END_REF]. In addition to familiarity, whether CRH increases or decreases activity depends on dose level [START_REF] Dunn | Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses?[END_REF]) and the light-dark cycle [START_REF] Valdez | Human urocortin 2: mild locomotor suppressive and delayed anxiolytic-like effects of a novel corticotropin-releasing factor related peptide[END_REF]. In particular, icv-administered CRH decreased activity in a novel open-field during the light cycle but increased it in the dark cycle [START_REF] Valdez | Human urocortin 2: mild locomotor suppressive and delayed anxiolytic-like effects of a novel corticotropin-releasing factor related peptide[END_REF]. CRH-induced activation in the familiar open-field was attenuated by icv administration of CRHR antagonists such as alpha-helical CRH-9-41 [START_REF] Britton | Corticotropin releasing factor (CRF) receptor antagonist blocks activating and 'anxiogenic' actions of CRF in the rat[END_REF][START_REF] Menzaghi | Characterization of a novel and potent corticotropin-releasing factor antagonist in rats[END_REF][START_REF] Spina | Behavioral effects of central administration of the novel CRF antagonist astressin in rats[END_REF] and D-Phe-CRH-12-41 (Menzaghi et al., 1994;[START_REF] Spina | Behavioral effects of central administration of the novel CRF antagonist astressin in rats[END_REF] as well as a more specific CRHR1 antagonist, antalarmin [START_REF] Zorrilla | Effects of antalarmin, a CRF type 1 receptor antagonist, on anxiety-like behavior and motor activation in the rat[END_REF]. But when antisense oligodeoxynucleotides corresponding to either CRHR1 or CRHR2 mRNA were infused into the lateral ventricle of rats via osmotic minipumps over 5 days, neither had any effect [START_REF] Liebsch | Differential behavioural effects of chronic infusion of CRH1 and CRH2 receptor antisense oligonucleotides into the rat brain[END_REF], presumably because blocking one receptor was compensated by the other.

CRHR agonists and antagonists

In a similar manner to CRH, icv-injected urocortin-1, mostly a CRHR2 agonist, reduced mouse exploratory activity in a novel open-field, an effect reversed by ipinjected diazepam or icv-injected alpha-helical CRH-9-41 [START_REF] Moreau | Urocortin, a novel neuropeptide with anxiogenic-like properties[END_REF].

Likewise, icv-administered urocortin-2, another CRHR2 agonist, decreased activity in a novel open-field (Skorzewska et al., 2011). In addition, icv-administered urocortin-1 and urotensin, yet another CRHR2 agonist, increased activity in a familiar open-field [START_REF] Jones | The behavioural effects of corticotropin-releasing factor-related peptides in rats[END_REF][START_REF] Spina | Appetite suppressant effects of urocortin, a CRF-related neuropeptide[END_REF], as did the CRHR2 agonist, sauvagine [START_REF] Jones | The behavioural effects of corticotropin-releasing factor-related peptides in rats[END_REF]. But yet icv-administered urocortin-2 increased activity in a familiar openfield only during the light not the dark part of the diurnal cycle [START_REF] Valdez | Human urocortin 2: mild locomotor suppressive and delayed anxiolytic-like effects of a novel corticotropin-releasing factor related peptide[END_REF], perhaps because of a ceiling effect. Icv-injected urocortin-3, also a selective CRHR2 agonist, even decreased photocell counts in a familiar open-field during the dark part of the diurnal cycle [START_REF] Valdez | Locomotor suppressive and anxiolytic-like effects of urocortin 3, a highly selective type 2 corticotropin-releasing factor agonist[END_REF].

Pharmacological studies are supplemented by Crh gene manipulations. Like CRH administration, three different Crh transgenic mouse models overexpressing the rat version of the gene had lower motor activity than wild-type in a novel open-field [START_REF] Kasahara | Altered behavioural adaptation in mice with neural corticotrophin-releasing factor overexpression[END_REF][START_REF] Stenzel-Poore | Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior[END_REF][START_REF] Van Gaalen | Effects of transgenic overproduction of CRH on anxiety-like behaviour[END_REF]. On the contrary, Crh null mutant mice lacking CRH displayed no change in motor activity in a novel open-field compared to wild-type with or without restraint stress, so that a compensatory mechanism appears to be at work, one or more genes taking over from the missing one [START_REF] Dunn | Behavioral responses to stress are intact in CRF-deficient mice[END_REF]. However, as expected, Crhr1 null mutant mice lacking CRHR1 were more active than wild-type in a novel open-field [START_REF] Timpl | Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1[END_REF], as were conditional Crhr1 null mutant mice lacking CRHR1 in the limbic system [START_REF] Müller | Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress[END_REF]. In contrast, Crhr2 null mutants did not differ from controls on motor activity in a novel open-field [START_REF] Coste | Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2[END_REF].

The anatomical basis of CRH-mediated effects on general activity has been initiated (Table 1). As found when injected icv, CRH injected in the amygdala, a brain area involved in many types of fear-related responses [START_REF] Tovote | Neuronal circuits for fear and anxiety[END_REF], decreased horizontal activity and rearing in a novel open-field in rats [START_REF] Liang | Intra-amygdala injections of corticotropin releasing factor facilitate inhibitory avoidance learning and reduce exploratory behavior in rats[END_REF], as did CRH injections in the Fr2 region of the frontal cortex [START_REF] Zieba | The behavioural and electrophysiological effects of CRF in rat frontal cortex[END_REF]. In contrast, CRH injected in the ventral tegmental area increased horizontal and vertical photocell counts in a novel open-field [START_REF] Kalivas | Neurochemical and behavioral effects of corticotropin-releasing factor in the ventral tegmental area of the rat[END_REF], although it usually does so in a familiar one. The more specific CRHR2 agonist, urocortin-1, administered in the supraoptic nucleus of the hypothalamus increased rearing and grooming episodes in a familiar open-field but without affecting locomotion and pretreatment with the CRHR2 antagonist, astressin-2B, normalized those effects [START_REF] Fatima | Urocortin 1 administered into the hypothalamic supraoptic nucleus affects openfield behaviour in rats[END_REF].

Other stress-related peptides

Ghrelin promotes growth hormone secretion via activation of the growth hormone secretagogue receptor in hypothalamus and pituitary gland [START_REF] Chanoine | Ghrelin and the growth hormone secretagogue receptor in growth and development[END_REF]. Unlike CRH, icv-injected ghrelin increased horizontal motor activity in a novel open-field in rats [START_REF] Carlini | Ghrelin increases anxiety-like behavior and memory retention in rats[END_REF]. However, icv-administered ghrelin decreased locomotor activity in a novel open-field when rats were evaluated over an unusually long period (20 hrs) [START_REF] Tang-Christensen | Central administration of ghrelin and agouti-related protein (83-132) increases food intake and decreases spontaneous locomotor activity in rats[END_REF], more than the 10 min used in the previous study. The ghrelin-induced increase in square crossings and rearing in the novel open-field was mitigated by icv-injected alpha-helical CRH-9-41, the CRHR antagonist [START_REF] Jaszberenyi | Mediation of the behavioral, endocrine and thermoregulatory actions of ghrelin[END_REF].

Glucocorticoids and mineralocorticoids

Glucocorticoids and mineralocorticoids alter open-field activity depending on number of injections and dose levels. Unlike CRH, acute 5 mg/kg ip corticosterone increased rat horizontal and vertical activity in a novel open-field [START_REF] Tenk | The effects of acute corticosterone on lithium chloride-induced conditioned place aversion and locomotor activity in rats[END_REF].

Horizontal activity was also elevated in a novel though not a familiar open-field after acute 2.5 or 5 mg/kg ip corticosterone (Sandi et al., 1996a). Moreover, horizontal activity increased in a novel open-field after acute 100 mg/kg sc corticosterone (Dickinson et al., 1985). On the contrary, no effect was found after acute 1 or 10 mg/kg ip corticosterone (Sandi et al., 1996a) or 2 mg/kg ip corticosterone [START_REF] Steketee | Pretreatment with corticosterone attenuates the nucleus accumbens dopamine response but not the stimulant response to cocaine in rats[END_REF] in a novel open-field. In an opposite manner to corticosterone, ip-injected metyrapone, a glucocorticoid synthesis inhibitor, decreased horizontal activity in a novel open-field [START_REF] Marinelli | Acute blockade of corticosterone secretion decreases the psychomotor stimulant effects of cocaine[END_REF], a result later confirmed and found as well in regard to vertical activity [START_REF] Canini | Metyrapone decreases locomotion acutely[END_REF]. But neither RU38486 (mifepristone), the glucocorticoid receptor antagonist, nor RU28318 (spironolactone), the mineralocorticoid receptor antagonist, had any effect on corticosterone-induced activation (Sandi et al., 1996a). Instead, ip or icv injections of the nitric oxide inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), was effective in preventing corticosterone-induced activation (Sandi et al., 1996b). But when acute corticosterone was infused in the nucleus pontis oralis (Table 1), distance traveled increased in a novel open-field and this effect was prevented by pretreatment in the same nucleus with either mifepristone or spironolactone [START_REF] Sandoval-Herrera | Corticosterone microinjected into nucleus pontis oralis increases tonic immobility in rats[END_REF].

While examining the effects of chronic corticosterone, one must take into account its synaptotoxic effects in the hippocampus when administered at 40 mg/kg sc for 60 days [START_REF] Tata | Synapse loss from chronically elevated glucocorticoids: relationship to neuropil volume and cell number in hippocampal area CA3[END_REF]. On one hand, a long-lasting 20 mg pellet of corticosterone for 21 days decreased motor activity in C57BL/6J and C57BL/6N mice exploring a novel open-field [START_REF] Sturm | Impact of chronic corticosterone application on depression-like behavior in C57BL/6N and C57BL/6J mice[END_REF]. A decrease was also found in rats exploring a novel open-field after 4-day treatment of 100 mg/kg sc corticosterone (Dickinson et al., 1985). On the other hand, a long-lasting 200 mg pellet for 21 days had no such effect in rats (Diniz et al., 2011). Although 40 mg/kg sc corticosterone for 21 days caused hypoactivity in a novel open-field in rats in one study [START_REF] Lee | Chronic administration of catechin decreases depression and anxiety-like behaviors in a rat model using chronic corticosterone injections[END_REF], the same dose, treatment time, open-field condition, and species had no effect in another [START_REF] Marks | Repeated exposure to corticosterone increases depression-like behavior in two different versions of the forced swim test without altering nonspecific locomotor activity or muscle strength[END_REF], and neither did a 22-day period of 40 mg/kg sc corticosterone [START_REF] Kalynchuk | Corticosterone increases depression-like behavior, with some effects on predator odor-induced defensive behavior, in male and female rats[END_REF]. In addition, 25 mg/kg sc corticosterone for 28 days did not affect horizontal and vertical activity [START_REF] Pego | Dissociation of the morphological correlates of stress-induced anxiety and fear[END_REF]. Nevertheless, home-cage hypoactivity was found in C57BL/6Ntac mice treated for 8 weeks with corticosterone in their drinking water [START_REF] Rainer | Beneficial behavioural and neurogenic effects of agomelatine in a model of depression/anxiety[END_REF]. While acute corticosterone sometimes increases activity in a novel open-field, chronic corticosterone sometimes causes the opposite effect, either effect seeming to appear within narrow dose ranges. Corticosterone-mediated hypoactivity may be more sensitive in more active mouse strains such as C57BL/6J than less active ones.

In addition to mature animals, the effects of chronic corticosterone have been examined during the neonatal period. Corticosterone administered sc post-partum in the mother rat increased offspring peripheral crossings in a novel open-field on postnatal (P) days 24-26 [START_REF] Brummelte | High post-partum levels of corticosterone given to dams influence postnatal hippocampal cell proliferation and behavior of offspring: A model of post-partum stress and possible depression[END_REF]. These findings are consistent with those of elevated wheel-running activity on P14-26 after long-lasting corticosterone pellet treatment on P2-14 in mice [START_REF] Howard | Increased voluntary running and decreased motor coordination in mice after neonatal corticosterone implantation[END_REF]) and elevated horizontal and vertical activity on P18-21 after acute dexamathesone sc treatment on P7 in rats [START_REF] Ferguson | Neonatal dexamethasone on day 7 causes mild hyperactivity and cerebellar stunting[END_REF]. However, a long-lasting pellet of corticosterone on P2-14 reduced mouse open-field activity at 2 and 4 months of age [START_REF] Howard | Increased voluntary running and decreased motor coordination in mice after neonatal corticosterone implantation[END_REF]. Likewise, when rat dams were injected sc with dexamethasone thoughout pregnancy or only the final week, adult offspring was less active than vehicle-treated rats [START_REF] Welberg | Prenatal glucocorticoid programming of brain corticosteroid receptors and corticotrophin-releasing hormone: possible implications for behaviour[END_REF].

Center zone exploration

The evaluation of anxiety levels in the open-field can best be ascertained by measuring central as opposed to peripheral exploration, the former being a more anxiogenic area as a result of the thigmotaxic (wall-hugging) tendencies of rats and mice to ensure survival in the wild [START_REF] Choleris | A detailed ethological analysis of the mouse open field test: effects of diazepam, chlordiazepoxide and an extremely low frequency pulsed magnetic field[END_REF][START_REF] Prut | The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review[END_REF].

When center measures are used, the open-field is almost always unfamiliar to the animal to maximize anxiety levels. Sometimes, an object is introduced in the center so that object exploration can be measured in addition to the exploration of place.

Benzodiazepines with anxiolytic properties in other assays increase entries or time spent in the center region, whereas antagonists at these receptors decrease these measures.

In an opposite manner to benzodiazepines, restraint stress decreased center region entries and duration in mice [START_REF] Henry | The effect of lateral septum corticotropinreleasing factor receptor 2 activation on anxiety is modulated by stress[END_REF]. However, no such effect in mice was found on center zone duration in another study [START_REF] Yoon | Chronic non-social stress affects depressive behaviors but not anxiety in mice[END_REF]. Chronic unpredictable mild stress even increased time spent in the center of the open-field [START_REF] Liu | Corticosterone reduces brain mitochondrial function and expression of mitofusin, BDNF in depression-like rodents regardless of exercise preconditioning[END_REF]. Effects on center region activity are also counter-intuitive.

Instead of decreasing center square activity, noise-light stress increased it [START_REF] Roth | Stress, behavioral arousal, and open field activity-a reexamination of emotionality in the rat[END_REF], as did either restraint or footshock stress [START_REF] Lee | Stress selectively influences center region activity of mice in an open field[END_REF][START_REF] Lee | The hippocampus and amygdala mediate the locomotor stimulating effects of corticotropin-releasing factor in mice[END_REF], presumably because stressed animals run around to escape the novel environment. Indeed, restraint or footshock stress increased peripheral activity, though in a different time-frame than the increase in central activity [START_REF] Lee | Stress selectively influences center region activity of mice in an open field[END_REF].

The degree of center area exploration depends on rodent strain. For example, F344/N rats had more center region activity than Harlan Sprague-Dawley rats [START_REF] Sternberg | Corticotropin releasing hormone related behavioral and neuroendocrine responses to stress in Lewis and Fischer rats[END_REF]. It also depends on neonatal handling, a critical modulator of the HPA response [START_REF] Meaney | Individual differences in hypothalamicpituitary-adrenal activity in later life and hippocampal aging[END_REF][START_REF] Zaletel | Chronic stress, hippocampus and parvalbumin-positive interneurons: what do we know so far?[END_REF], generally leading to anxiolytic effects [START_REF] Raineki | Neonatal handling: an overview of the positive and negative effects[END_REF]. Relative to controls, neonatally handled rats had higher glucocorticoid receptor binding in the hippocampus [START_REF] Meaney | Neonatal handling alters adrenocortical negative feedback sensitivity and hippocampal type II glucocorticoid receptor binding in the rat[END_REF], lower glucocorticoid secretion in response to stress [START_REF] Meaney | Effect of neonatal handling on age-related impairments associated with the hippocampus[END_REF], and a higher degree of exploration in the center of the open-field [START_REF] Caldji | The effects of early rearing environment on the development of GABAA and central benzodiazepine receptor levels and novelty-induced fearfulness in the rat[END_REF][START_REF] Madruga | Early handling, but not maternal separation, decreases emotional responses in two paradigms of fear without changes in mesolimbic dopamine[END_REF][START_REF] Padoin | Long-lasting effects of neonatal handling stimulation in the behavior of rats[END_REF], the latter result also found in boars [START_REF] Weaver | Neonatal handling permanently alters hypothalamic-pituitary-adrenal axis function, behaviour, and body weight in boars[END_REF].

CRH agonists and antagonists

After injection via the icv route in rats, CRH decreased approaches to a food pellet placed in the center of the open-field and increased grooming, concordant with an anxiogenic response [START_REF] Britton | Intraventricular corticotropin-releasing factor enhances behavioral effects of novelty[END_REF]. Icv-injected CRH reduced center region entries in rats without affecting peripheral activity, an anxiogenic-like pattern reversed by icv administration of the CRHR antagonist, alpha-helical CRH-9-41 [START_REF] Kumar | Alpha-helical CRF blocks differential influence of corticotropin releasing factor (CRF) on appetitive and aversive memory retrieval in rats[END_REF] or antisense targeting with oligonucleotides against CRHR1 mRNA [START_REF] Skutella | Corticotropin-releasing hormone receptor (type I) antisense targeting reduces anxiety[END_REF]. Icv-injected CRH also decreased center zone duration in rats [START_REF] Campbell | Differential regulation of behavioral, genomic, and neuroendocrine responses by CRF infusions in rats[END_REF] but increased center zone activity without affecting peripheral activity in the genetically anxious Balb/c mouse strain, an effect reversed by ipinjected diazepam [START_REF] Lee | Stress and corticotropin-releasing factor potentiate center region activity of mice in an open field[END_REF]. Moreover, icv-administered CRH increased central but not peripheral activity in hypophysectomized rats [START_REF] Veldhuis | Differential behavioral actions of corticotropin-releasing factor (CRF)[END_REF]. Thus, like stress, CRH appears to increase activity in the center of the openfield despite decreasing entries and duration. On the contary, null mutant mice lacking CRH binding protein did not differ from wild-type in center zone entries and duration [START_REF] Karolyi | Altered anxiety and weight gain in corticotropin-releasing hormone-binding protein-deficient mice[END_REF], indicating a compensatory action by another gene. A cue may be provided by the increase in center zone distance and duration noted under icv-administered CRH after acute iv administration of teneurin C-terminal associated peptide-1 (TCAP-1) (Al Chawaf et al., 2007).

Like CRH, icv-administered cortagine, a CRHR1 agonist [START_REF] Farrokhi | Cortagine: behavioral and autonomic function of the selective CRF receptor subtype 1 agonist[END_REF], decreased center zone duration in C57BL/6J mice (Sherrin et al., 2009).

Uncertainty arises as to the influence of CRHR2. Icv-injected urocortin-3, the CRHR2 agonist, augmented center region entries and duration in C57BL/6 mice [START_REF] Venihaki | Urocortin III, a brain neuropeptide of the corticotropin-releasing hormone family: modulation by stress and attenuation of some anxiety-like behaviours[END_REF]). Yet icv-injected anti-sauvagine-30, the CRHR2 antagonist, also increased center zone duration in Balb/c mice [START_REF] Pelleymounter | Pharmacological evidence supporting a role for central corticotropin-releasing factor(2) receptors in behavioral, but not endocrine, response to environmental stress[END_REF]. This paradox may be due to the different mouse strains used, as C57BL/6 mice are generally less anxious than Balb/c [START_REF] Lalonde | Relations between open-field, elevated plusmaze, and emergence tests as displayed by C57BL/6J and BALB/c mice[END_REF]. Although one Crhr2 null mutant mouse model lacking CRHR2 showed more center zone entries than wild-type [START_REF] Kishimoto | Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2[END_REF], a different Crhr2 knockout mouse model showed fewer center region entries and lesser duration [START_REF] Bale | Mice deficient for corticotropinreleasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress[END_REF] while a third did not differ from controls on center zone duration [START_REF] Coste | Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2[END_REF].

Limbic regions are implicated in CRH-mediated effects on center region behaviors (Table 2). CRH augmented center zone activity in Balb/c mice injected in hippocampus but not in amygdala or caudate nucleus [START_REF] Lee | The hippocampus and amygdala mediate the locomotor stimulating effects of corticotropin-releasing factor in mice[END_REF].

Lentivirus-induced CRH overexpression for 4 months in the central nucleus of the amygdala but not the bed nucleus of the stria terminalis increased center region entries in non-stressed rats as well as center region entries and duration in rats preexposed to restraint stress [START_REF] Regev | Prolonged and site-specific over-expression of corticotropinreleasing factor reveals differential roles for extended amygdala nuclei in emotional regulation[END_REF]). Yet acute CRH knockdown with RNA oligonucleotides in the central nucleus of the amygdala had no effect on center zone entries and duration, implying the existence of a compensatory mechanism [START_REF] Callahan | Inhibition of corticotropin releasing factor expression in the central nucleus of the amygdala attenuates stress-induced behavioral and endocrine responses[END_REF]. The CHRHR2 agonist, urocortin-2, infused in the lateral septum potentiated immobilization stress-induced decreases in center zone entries and duration in mice [START_REF] Henry | The effect of lateral septum corticotropinreleasing factor receptor 2 activation on anxiety is modulated by stress[END_REF].

When basal ganglia are examined, CRH infused in the shell region of the nucleus accumbens reduced center zone duration without affecting general ambulation in the open-field [START_REF] Chen | Corticotropin-releasing factor in the nucleus accumbens shell induces swim depression, anxiety, and anhedonia along with changes in local dopamine/acetylcholine balance[END_REF]. In an opposite manner, the CRHR1 antagonist, NBI30775, infused in the external part of the globus pallidus increased center region entries [START_REF] Sztainberg | An anxiolytic role for CRF receptor type 1 in the globus pallidus[END_REF]). Yet, paradoxically, knockdown of CRHR1 mRNA expression by a lentiviral-based system in the same brain region decreased center region entries without changing total distance traveled [START_REF] Sztainberg | An anxiolytic role for CRF receptor type 1 in the globus pallidus[END_REF].

In summary, the hippocampus, amygdala, lateral septum, nucleus accumbens, and lateral globus pallidus appear involved in CRH-mediated anxiety in the central zone of the open-field. The amygdala and hippocampus are anatomically interrelated and the main output from the hippocampal formation, the subiculum, strongly projects to lateral septum and nucleus accumbens [START_REF] Witter | Hippocampal formation[END_REF]. The lateral septum mainly expresses CRHR2 rather than CRHR1 [START_REF] Van Pett | Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse[END_REF], which likely explains the anxiogenic response of the CHRHR2 agonist. Of note as well are findings that the lateral septum receives dense projections from the medial amygdala [START_REF] Canteras | Organization of projections from the medial nucleus of the amygdala: a PHAL study in the rat[END_REF] and the bilateral connections between the lateral septum and the hypothalamus [START_REF] Risold | Connections of the rat lateral septal complex[END_REF]. The effects of the lateral globus pallidus may be explained by its high levels of CRHR1 expression and its afferents from the central amygdala (Shinonaga et al., 1992).

Glucocorticoids and mineralocorticoids

On one hand, acute 20 but not 5 mg/kg sc corticosterone increased center region entries, duration, and distance travelled in rats [START_REF] Skorzewska | The effects of acute and chronic administration of corticosterone on rat behavior in two models of fear responses, plasma corticosterone concentration, and c-Fos expression in the brain structures[END_REF].

Center zone duration also increased after acute 1 mg/kg sc corticosterone in rats when an object was placed inside, an effect prevented by icv-administered spironolactone, the mineralocorticoid receptor antagonist, but not by mifepristone, the glucocorticoid receptor antagonist [START_REF] Oitzl | The effect of corticosterone on reactivity to spatial novelty is mediated by central mineralocorticosteroid receptors[END_REF]. On the other hand, acute 0.5 mg/kg ip corticosterone decreased center zone duration in C57BL/6 mice [START_REF] Espallergues | HDAC6 regulates glucocorticoid receptor signaling in serotonin pathways with critical impact on stress resilience[END_REF]. In contrast to acute administration, chronic corticosterone mostly causes anxiogenic effects. In particular, 5 and 20 mg/kg sc corticosterone for 25 days decreased plasma corticosterone concentrations (via feedback inhibition) in rats and decreased center zone entries, duration, and distance without affecting total distance traveled [START_REF] Skorzewska | The effects of acute and chronic administration of corticosterone on rat behavior in two models of fear responses, plasma corticosterone concentration, and c-Fos expression in the brain structures[END_REF]. Likewise, 7-day corticosterone treatment in drinking water decreased center zone entries and duration in C57BL/6NTac mice (David et al., 2009) and 21-day corticosterone treatment in drinking water decreased center zone duration and elevated latencies before entering the center zone in rats (Donner et al., 2012). The 21-day corticosterone treatment in drinking water also decreased center region entries without changing general activity, an effect prevented by combined sc treatment with mifepristone and spironolactone [START_REF] Fan | Corticosterone administration up-regulated expression of norepinephrine transporter and dopamine β-hydroxylase in rat locus coeruleus and its terminal regions[END_REF]. Although a long-lasting corticosterone pellet for 21 days decreased center zone entries in C57BL/6N mice, it had no effect on the closely allied C57BL/6J strain [START_REF] Sturm | Impact of chronic corticosterone application on depression-like behavior in C57BL/6N and C57BL/6J mice[END_REF]. Neither did a long-lasting corticosterone pellet for 21 days had any effect in C57BL/6J mice on center zone duration (Demuyser et al., 2016). In addition, 40 mg/kg sc corticosterone for 21 days had no effect in rats on center zone entries [START_REF] Kalynchuk | Corticosterone increases depression-like behavior, with some effects on predator odor-induced defensive behavior, in male and female rats[END_REF] or center zone entries, rearing, or time spent freezing [START_REF] Gregus | Effect of repeated corticosterone injections and restraint stress on anxiety and depression-like behavior in male rats[END_REF], and at 20 mg/kg sc on center zone duration [START_REF] Yoon | Chronic non-social stress affects depressive behaviors but not anxiety in mice[END_REF].

Moreover, 25 mg/kg sc corticosterone for 28 days did not affect center zone duration in rats [START_REF] Pego | Dissociation of the morphological correlates of stress-induced anxiety and fear[END_REF], and neither did 20 mg/kg sc corticosterone for 40 days [START_REF] Liu | Corticosterone reduces brain mitochondrial function and expression of mitofusin, BDNF in depression-like rodents regardless of exercise preconditioning[END_REF]. Thus, corticosterone-mediated anxiogenic effects depend on subtle differences in mouse strains as well as narrow dose ranges and treatment time.

Center zone duration decreased in young offspring of adrenalectomized dams replaced with corticosterone relative to sham-operated controls [START_REF] Wilcoxon | Maternal glucocorticoid deficit affects hypothalamic-pituitary-adrenal function and behavior of rat offspring[END_REF]. But offspring from corticosterone-treated dams had equivalent central zone crossings on P24-26 relative to control offspring [START_REF] Brummelte | High post-partum levels of corticosterone given to dams influence postnatal hippocampal cell proliferation and behavior of offspring: A model of post-partum stress and possible depression[END_REF].

Dexamethasone administered sc in neonatal rats and tested at 2.5-3 months had higher start latencies from the center region while the more slowly metabolized ACTH-(4-9) analogue, ORG2766, had no such effect [START_REF] Felszeghy | Behavioral depression: opposite effects of neonatal dexamethasone and ACTH-(4-9) analogue (ORG 2766) treatments in the rat[END_REF].

Likewise, ORG2766 injected sc in neonatal rats and tested at 3 months had no effect on center zone entries and duration [START_REF] Horvath | Early postnatal treatment with ACTH4-9 analog ORG 2766 improves adult spatial learning but does not affect behavioural stress reactivity[END_REF].

The icv administration of obestatin, a peptide found in the pituitary gland, decreased central ambulation in the open-field, an effect reversed by [d-Lys3]-GHRP6, a ghrelin receptor antagonist [START_REF] Szakacs | The effect of obestatin on anxiety-like behaviour in mice[END_REF]. Rats chronically administered with osmotic minipumps with the mineralocorticoid receptor agonist, aldosterone, entered less often, spent less time, and were less active in the central area [START_REF] Hlavacova | Chronic treatment with the mineralocorticoid hormone aldosterone results in increased anxiety-like behavior[END_REF].

The anatomical basis of glucocorticoid and mineralocorticoid receptormediated effects has been initiated (Table 2). Infusion of viral-mediated short hairpin RNA targeting against the glucocorticoid receptor in prelimbic cortex after chronic variable stress increased center and peripheral activity without changing center region duration, while infusion in infralimbic cortex had no impact on center zone duration or activity [START_REF] Mcklveen | Role of prefrontal cortex glucocorticoid receptors in stress and emotion[END_REF]. There was also no change in open zone duration after viral-mediated deletion of glucocorticoid receptors in the dorsal raphe [START_REF] Vincent | Glucocorticoid receptor deletion from the dorsal raphé nucleus of mice reduces dysphoria-like behavior and impairs hypothalamic-pituitary-adrenocortical axis feedback inhibition[END_REF]. The influence of the mineralocorticoid as opposed to the glucocorticoid receptor on this behavior is indicated by the finding that intrahippocampal infusion of spironolactone but not mifepristone increased center zone duration [START_REF] Bitran | Corticosterone is permissive to the anxiolytic effect that results from the blockade of hippocampal mineralocorticoid receptors[END_REF]. The anxiolytic action of spironolactone was eliminated in adrenalectomized rats or those pretreated with an ip injection of dexamethasone, perhaps because complete occupation of the mineralocorticoid site is necessary for the anxiolytic effect to occur, a state presumably compromised by adrenalectomy or occupation by a glucocorticoid receptor agonist. On the contrary, chronic sc treatment with another mineralocorticoid receptor antagonist, eplerenone, had no effect on center zone entries [START_REF] Hlavacova | Eplerenone, a selective mineralocorticoid receptor blocker, exerts anxiolytic effects accompanied by changes in stress hormone release[END_REF].

Hole-board

As found in the open-field [START_REF] Campbell | Differential regulation of behavioral, genomic, and neuroendocrine responses by CRF infusions in rats[END_REF], exposure to a hole-board increased plasma corticosterone concentrations in rats [START_REF] File | The rat corticosterone response: habituation and modification by chlordiazepoxide[END_REF], a noveltyinduced effect potentiated by anxiogenic agents such as the benzodiazepine receptor inverse agonist, FG7142, as well as benzodiazepine receptor antagonists, CGS8216 and Ro15-1788 (flumazenil) (Pellow and File, 1985). In an opposite mannner, divers agonists of the gamma-amino-butyric acid (GABA)-benzodiazepine receptor complex increased hole-board exploration in mice [START_REF] Bhatt | Anxiolytic-like effect of Nn-butyl-3-methoxyquinoxaline-2-carboxamide (60) in experimental mouse models of anxiety[END_REF]Bilkei-Gorzoa and Gyertyan, 1996;[START_REF] Do-Rego | Comparisons between anxiety tests for selection of anxious and non anxious mice[END_REF][START_REF] Kliethermes | Pharmacological and genetic influences on hole-board behaviors in mice[END_REF][START_REF] Nolan | The effects of benzodiazepines on the behaviour of mice on a hole-board[END_REF][START_REF] Takeda | Changes in head-dipping behavior in the hole-board test reflect the anxiogenic and/or anxiolytic state in mice[END_REF] and rats [START_REF] Seo | Anxiolytic-like effects of obovatol isolated from Magnolia obovata: involvement of GABA/benzodiazepine receptors complex[END_REF]. One of these, chlordiazepoxide, increased hole-board exploration under bright but not dark conditions when the level of exploration was maximal and thus liable to a ceiling effect [START_REF] Bilkei-Gorzo | Some doubts about the basic concept of hole-board test[END_REF]. Rather than being only an estimate of anxiety, head-dipping sometimes constitutes a component of escape attempt depending on the degree of environmental stress such as room brightness [START_REF] Bilkei-Gorzo | Some doubts about the basic concept of hole-board test[END_REF][START_REF] Brown | The exploratory behaviour of rats in the holeboard apparatus: is head-dipping a valid measure of neophilia?[END_REF].

CRHR agonists and antagonists

In an opposite manner to benzodiazepines, icv-injected CRH reduced holeboard exploration irrespective of whether the rats were hypophysectomized (Adamec et al., 1991). Also as expected, hole pokes diminished in transgenic mice overexpressing Crh [START_REF] Van Gaalen | Effects of transgenic overproduction of CRH on anxiety-like behaviour[END_REF].

Glucocorticoids and mineralocorticoids

Icv administration of urotensin-2, which decreases corticosterone secretion from cultured adrenocortical cells, an effect abolished by an antagonist of the urotensin receptor (Albertin et al., 2006), decreased head-dips without affecting motor activity in mice [START_REF] Do-Rego | Behavioral effects of urotensin-II centrally administered in mice[END_REF][START_REF] Matsumoto | Intracerebroventricular administration of urotensin II promotes anxiogenic-like behaviors in rodents[END_REF].

Multicompartment chamber

The exploration of novel stimuli placed in a multicompartment chamber has been used to estimate anxiety levels [START_REF] Berridge | A corticotropin-releasing factor antagonist reverses the stress-induced changes of exploratory behavior in mice[END_REF]. The main measure used is time spent in contact with novel stimuli.

CRHR agonists and antagonists

Either icv-administered CRH or restraint stress reduced times normal [START_REF] Berridge | A corticotropin-releasing factor antagonist reverses the stress-induced changes of exploratory behavior in mice[END_REF] or hypophysectomized [START_REF] Berridge | CRF and restraint-stress decrease exploratory behavior in hypophysectomized mice[END_REF] mice spent in contact with novel stimuli placed in the multicompartment chamber. The anxiogenic effect of restraint stress was reversed by icv administration of the CRH receptor antagonist, alpha-helical CRH-9-41 [START_REF] Berridge | A corticotropin-releasing factor antagonist reverses the stress-induced changes of exploratory behavior in mice[END_REF].

Nevertheless, Crh-deficient mice behaved normally in the multicompartment chamber with or without restraint stress, implying a compensatory action from another gene [START_REF] Dunn | Behavioral responses to stress are intact in CRF-deficient mice[END_REF][START_REF] Weninger | Stress-induced behaviors require the corticotropin-releasing hormone (CRH) receptor, but not CRH[END_REF].

To investigate the anatomical basis of CRH-induced downregulation of exploratory activity in the multicompartment chamber, cold cream plugs were applied to different regions in rat brain [START_REF] Spadaro | Corticotropinreleasing factor acts via a third ventricle site to reduce exploratory behavior in rats[END_REF]. When the cerebral aqueduct was blocked, CRH injected in the lateral but not the fourth ventricle decreased exploratory behavior. Blocking the third ventricle prevented the effect of lateral ventricle administration, especially the anteroventral portion, where lies the organum vasculosum laminae terminalis (OVLT), involved in the pressor response. It is also possible that CRHR1 located on paraventricular CRH neurons affected anxiety via positive feedback control [START_REF] Mansi | Regulation of corticotropin-releasing factor type 1 (CRF1) receptor messenger ribonucleic acid in the paraventricular nucleus of rat hypothalamus by exogenous CRF[END_REF].

Glucocorticoids and mineralocorticoids

To our knowledge, the effects of glucocorticoids and mineralocorticoids on the multicompartment chamber have not been examined.

Elevated plus-maze

The elevated plus-maze contains two anxiogenic open arms intersecting two safer enclosed arms [START_REF] Fernandes | The influence of open arm ledges and maze experience in the elevated plus-maze[END_REF][START_REF] Hogg | A review of the validity and variability of the elevated plus-maze as an animal model of anxiety[END_REF][START_REF] Kulkarni | Elevated plus-maze: a novel psychobehavioral tool to measure anxiety in rodents[END_REF]Pellow et al., 1985;[START_REF] Walf | The use of the elevated plus maze as an assay of anxiety-related behavior in rodents[END_REF]. To prevent rodents from falling off the open arms, tiny ledges are put up along the sides, a procedure that subtly influences drug effects in multiple trial paradigms [START_REF] Fernandes | The influence of open arm ledges and maze experience in the elevated plus-maze[END_REF]. As found in the open-field [START_REF] Campbell | Differential regulation of behavioral, genomic, and neuroendocrine responses by CRF infusions in rats[END_REF]) and hole-board (Pellow and File, 1985), rats continuously exposed to the open arms had higher plasma corticosterone levels than those continuously exposed to control conditions, in this case either the enclosed arms (Pellow et al., 1985) or their home-cage [START_REF] File | Raised corticosterone in the rat after exposure to the elevated plus-maze[END_REF]. Elevated plus-maze exposure also increased plasma ACTH (Appenrodt et al., 1999;[START_REF] Keck | The anxiolytic effect of the CRH(1) receptor antagonist R121919 depends on innate emotionality in rats[END_REF] and CRH mRNA levels in the central nucleus of the amygdala (Shepard et al., 2003). The paradigm is susceptible to strain differences, since, for example, open arm exploration was higher in C57BL/6JOlaHsd than DBA/2OlaHsd mice [START_REF] Thoeringer | The temporal dynamics of intrahippocampal corticosterone in response to stress-related stimuli with different emotional and physical load: an in vivo microdialysis study in C57BL/6 and DBA/2 inbred mice[END_REF] and Wistar or Wistar Kyoto than F344 rats, perhaps due to the higher basal CRH mRNA levels found in the central nucleus of the amygdala of Wistar Kyoto [START_REF] Shepard | Strain differences in anxiety-like behavior: association with corticotropin-releasing factor[END_REF]. The open/total arm ratio of exploration has pharmacological validity as a specific measure of anxiety, since higher values were obtained after the administration of benzodiazepines [START_REF] Bhatt | Anxiolytic-like effect of Nn-butyl-3-methoxyquinoxaline-2-carboxamide (60) in experimental mouse models of anxiety[END_REF][START_REF] Conti | Mouse strain differences in the behavioral effects of corticotropin-releasing factor (CRF) and the CRF antagonist alpha-helical CRF9-41[END_REF][START_REF] Griebel | Characterization of the behavioral profile of the non-peptide CRF receptor antagonist CP-154,526 in anxiety models in rodents: comparison with diazepam and buspirone[END_REF][START_REF] Hodgson | Comparison of the V1b antagonist, SSR149415, and the CRF1 antagonist, CP-154,526, in rodent models of anxiety and depression[END_REF][START_REF] Lalonde | Relations between open-field, elevated plusmaze, and emergence tests in C57BL/6J and BALB/c mice injected with GABAand 5HT-anxiolytic agents[END_REF][START_REF] Lelas | Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats[END_REF][START_REF] Millan | Anxiolytic properties of the selective, non-peptidergic corticotropin-releasing factor (CRF)1 antagonists, CP154,526 and DMP 695: a comparison to other classes of anxiolytic agent[END_REF]Pellow and File, 1985;[START_REF] Ramos | A multiple-test study of anxiety-related behaviours in six inbred rat strains[END_REF][START_REF] Rochford | Behavioral reactivity to aversive stimuli in a transgenic mouse model of impaired glucocorticoid (type II) receptor function: effects of diazepam and FG-7142[END_REF][START_REF] Seo | Anxiolytic-like effects of obovatol isolated from Magnolia obovata: involvement of GABA/benzodiazepine receptors complex[END_REF][START_REF] Stock | A lack of tolerance to the anxiolytic effects of diazepam on the plus-maze: comparison of male and female rats[END_REF], ethanol [START_REF] Durcan | Interactions of 5HT reuptake inhibitors and ethanol in tests of exploration and anxiety[END_REF], and divers olfactory substances [START_REF] Tsang | A systematic review on the anxiolytic effects of aromatherapy on rodents under experimentally induced anxiety models[END_REF].

As found for center zone exploration in the open-field (section 2.2), neonatal handling increased open arm exploration [START_REF] Raineki | Neonatal handling: an overview of the positive and negative effects[END_REF]. In contrast, restraint, resident intruder, or swim stress decreased open arm exploration [START_REF] Heinrichs | Anti-stress action of a corticotropin-releasing factor antagonist on behavioral reactivity to stressors of varying type and intensity[END_REF][START_REF] Heinrichs | Brain penetrance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist[END_REF], as did footshock stress [START_REF] Calvo | Glucocorticoid and mineralocorticoid receptors are involved in the facilitation of anxiety-like response induced by restraint[END_REF][START_REF] Lim | Enhancement of anxiety and modulation of TH and pERK expressions in amygdala by repeated injections of corticosterone[END_REF] or a combination of stress conditions [START_REF] Han | Expression of amygdala mineralocorticoid receptor and glucocorticoid receptor in the single-prolonged stress rats[END_REF]. Stress-induced effects seem mediated by corticosterone because the restraint stress-induced decrease in open arm entries and duration was prevented by metyrapone, a 11-ß-hydroxylase inhibitor that blocks corticosterone synthesis [START_REF] Calvo | Glucocorticoid and mineralocorticoid receptors are involved in the facilitation of anxiety-like response induced by restraint[END_REF]. In addition, the anxiogenic action of resident intruder stress [START_REF] Calfa | Glucocorticoid receptors in lateral septum are involved in the modulation of the emotional sequelae induced by social defeat[END_REF][START_REF] Calfa | Involvement of the lateral septum and the ventral Hippocampus in the emotional sequelae induced by social defeat: role of glucocorticoid receptors[END_REF] was prevented by the glucocorticoid receptor antagonist, mifepristone, but not the mineralocorticoid receptor antagonist, ZK91587, injected in the lateral septum [START_REF] Calfa | Glucocorticoid receptors in lateral septum are involved in the modulation of the emotional sequelae induced by social defeat[END_REF].

Moreover, the swim stress-induced decrease in open arm time was counteracted by the CRHR1 antagonist, CP376395, but not the CRHR2 antagonist, astressin-2B, injected in the bed nucleus of the stria terminalis [START_REF] Tran | Importance of CRF receptor-mediated mechanisms of the bed nucleus of the stria terminalis in the processing of anxiety and pain[END_REF].

CRH receptor agonists and antagonists

Intracerebroventricular and peripheral injections

In an opposite fashion to benzodiazepines, icv-administered CRH has often been shown to reduce open arm exploration in the elevated plus-maze [START_REF] Adamec | The effects of CRF and alpha-helical CRF on anxiety in normal and hypophysectomized rats[END_REF]Adamec et al., 1991;[START_REF] Baldwin | CRF antagonist reverses the "anxiogenic" response to ethanol withdrawal in the rat[END_REF][START_REF] Bruchas | CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior[END_REF][START_REF] Buwalda | Physiological and behavioral effects of chronic intracerebroventricular infusion of corticotropin-releasing factor in the rat[END_REF][START_REF] Jones | The behavioural effects of corticotropin-releasing factor-related peptides in rats[END_REF][START_REF] Kagamiishi | Hippocampal serotonergic system is involved in anxiety-like behavior induced by corticotropin-releasing factor[END_REF][START_REF] Kishimoto | Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2[END_REF][START_REF] Moreau | Urocortin, a novel neuropeptide with anxiogenic-like properties[END_REF][START_REF] Pelleymounter | Behavioral and neuroendocrine effects of the selective CRF2 receptor agonists urocortin II and urocortin III[END_REF][START_REF] Rodi | Functional antagonism between nociceptin/orphanin FQ (N/OFQ) and corticotropin-releasing factor (CRF) in the rat brain: evidence for involvement of the bed nucleus of the stria terminalis[END_REF][START_REF] Song | Behavioral, neurochemical, and immunological responses to CRF administration: is CRF a mediator of stress?[END_REF][START_REF] Spina | Appetite suppressant effects of urocortin, a CRF-related neuropeptide[END_REF][START_REF] Spina | Behavioral effects of central administration of the novel CRF antagonist astressin in rats[END_REF][START_REF] Tan | Repeated intracerebral teneurin C-terminal associated peptide (TCAP)-1 injections produce enduring changes in behavioral responses to corticotropin-releasing factor (CRF) in rat models of anxiety[END_REF][START_REF] Tezval | Cortagine, a specific agonist of corticotropin-releasing factor receptor subtype 1, is anxiogenic and antidepressive in the mouse model[END_REF][START_REF] Venihaki | Urocortin III, a brain neuropeptide of the corticotropin-releasing hormone family: modulation by stress and attenuation of some anxiety-like behaviours[END_REF], an effect mitigated by icv-administered CRHR antagonists such as alphahelical CRH-9-41 [START_REF] Kagamiishi | Hippocampal serotonergic system is involved in anxiety-like behavior induced by corticotropin-releasing factor[END_REF] and astressin [START_REF] Spina | Behavioral effects of central administration of the novel CRF antagonist astressin in rats[END_REF], CRHR1

antagonists such as po [START_REF] Okuyama | Receptor binding, behavioral, and electrophysiological profiles of nonpeptide corticotropinreleasing factor subtype 1 receptor antagonists CRA1000 and CRA1001[END_REF] or ip [START_REF] Zorrilla | Effects of antalarmin, a CRF type 1 receptor antagonist, on anxiety-like behavior and motor activation in the rat[END_REF] administered antalarmin and po-administered CRA1000H2SO4 or CRA1001H2SO4 [START_REF] Okuyama | Receptor binding, behavioral, and electrophysiological profiles of nonpeptide corticotropinreleasing factor subtype 1 receptor antagonists CRA1000 and CRA1001[END_REF] as well as icv-injected antisense targeting with oligodeoxynucleotides against CRHR1 mRNA [START_REF] Skutella | Corticotropin-releasing hormone receptor (type I) antisense targeting reduces anxiety[END_REF]. The anxiogenic impact of icv-administered CRH was observed regardless of whether rats were hypophysectomized and therefore independent of corticosterone [START_REF] Adamec | The effects of CRF and alpha-helical CRF on anxiety in normal and hypophysectomized rats[END_REF].

Other CRHR1 agonists possess anxiogenic properties in the elevated plusmaze. In particular, icv-administered stressin-1 decreased open arm duration [START_REF] Bruchas | CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior[END_REF] and icv-administered cortagine decreased open arm entries and duration (Sherrin et al., 2009;[START_REF] Tezval | Cortagine, a specific agonist of corticotropin-releasing factor receptor subtype 1, is anxiogenic and antidepressive in the mouse model[END_REF]. There is mixed evidence regarding CRHR2 agonists. Open arm exploration decreased after icv-administered urocortin-1 [START_REF] Jones | The behavioural effects of corticotropin-releasing factor-related peptides in rats[END_REF][START_REF] Moreau | Urocortin, a novel neuropeptide with anxiogenic-like properties[END_REF][START_REF] Spina | Time-dependent induction of anxiogenic-like effects after central infusion of urocortin or corticotropin-releasing factor in the rat[END_REF]. In the same maze configuration, urocortin-1 had this anxiogenic effect at 30 [START_REF] Spina | Time-dependent induction of anxiogenic-like effects after central infusion of urocortin or corticotropin-releasing factor in the rat[END_REF] but not 5 [START_REF] Spina | Appetite suppressant effects of urocortin, a CRF-related neuropeptide[END_REF] min after injection. Although open arm duration declined after icv-administered urocortin-2 in Balb/c mice [START_REF] Pelleymounter | Behavioral and neuroendocrine effects of the selective CRF2 receptor agonists urocortin II and urocortin III[END_REF], icvinjected urocortin-3 had no effect in C57BL/6 mice either alone or after restraint stress [START_REF] Venihaki | Urocortin III, a brain neuropeptide of the corticotropin-releasing hormone family: modulation by stress and attenuation of some anxiety-like behaviours[END_REF]. There is even evidence that icv-injected urocortin-2 [START_REF] Valdez | Human urocortin 2: mild locomotor suppressive and delayed anxiolytic-like effects of a novel corticotropin-releasing factor related peptide[END_REF] or urocortin-3 [START_REF] Valdez | Locomotor suppressive and anxiolytic-like effects of urocortin 3, a highly selective type 2 corticotropin-releasing factor agonist[END_REF] in rats or urocortin-3 in mice [START_REF] Telegdy | Involvement of transmitters in the anxiolytic action of urocortin 3 in mice[END_REF] increased open arm exploration, although the latter had no effect in subsequent studies [START_REF] Bruchas | CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior[END_REF][START_REF] Cipriano | CRF receptor type 1 (but not type 2) located within the amygdala plays a role in the modulation of anxiety in mice exposed to the elevated plus maze[END_REF][START_REF] Venihaki | Urocortin III, a brain neuropeptide of the corticotropin-releasing hormone family: modulation by stress and attenuation of some anxiety-like behaviours[END_REF].

In contrast to agonists, CRHR antagonists possess anxiolytic properties in the elevated plus-maze, though dependent on post-injection interval and rodent strain. Indeed, icv-injected 50 μg alpha-helical CRH-9-41 increased open arm duration in Wistar rats when tested at the 60 min (Adamec et al., 1991) but not the 30 min [START_REF] Baldwin | CRF antagonist reverses the "anxiogenic" response to ethanol withdrawal in the rat[END_REF] post-injection interval. Although icv-injected alpha-helical CRH-9-41 increased open arm entries and duration in Balb/c mice, no such effect occurred in NIH Swiss, CD, or CF-I mice [START_REF] Conti | Mouse strain differences in the behavioral effects of corticotropin-releasing factor (CRF) and the CRF antagonist alpha-helical CRF9-41[END_REF]. Nevertheless, anxiolytic effects are found with CRHR1 antagonists, since po-administered DMP904 increased open arm duration [START_REF] Lelas | Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats[END_REF] and ip-injected CP-154,526, an analog of antalarmin [START_REF] Schulz | CP-154,526: a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors[END_REF][START_REF] Seymour | The pharmacology of CP-154,526, a non-peptide antagonist of the CRH1 receptor: a review[END_REF], increased open arm entries and duration [START_REF] Lundkvist | A non-peptidic corticotropin releasing factor receptor antagonist attenuates fever and exhibits anxiolytic-like activity[END_REF],. But other studies have shown no effect in the elevated plusmaze after ip-injected CP-154,526 [START_REF] Griebel | Characterization of the behavioral profile of the non-peptide CRF receptor antagonist CP-154,526 in anxiety models in rodents: comparison with diazepam and buspirone[END_REF][START_REF] Hodgson | Comparison of the V1b antagonist, SSR149415, and the CRF1 antagonist, CP-154,526, in rodent models of anxiety and depression[END_REF][START_REF] Millan | Anxiolytic properties of the selective, non-peptidergic corticotropin-releasing factor (CRF)1 antagonists, CP154,526 and DMP 695: a comparison to other classes of anxiolytic agent[END_REF] or antalarmin [START_REF] Zorrilla | Effects of antalarmin, a CRF type 1 receptor antagonist, on anxiety-like behavior and motor activation in the rat[END_REF] when no pre-stress condition was applied, and neither did sc-injected DMP695 [START_REF] Millan | Anxiolytic properties of the selective, non-peptidergic corticotropin-releasing factor (CRF)1 antagonists, CP154,526 and DMP 695: a comparison to other classes of anxiolytic agent[END_REF], ip-injected CRA1000 [START_REF] Harro | The effects of CRA 1000, a nonpeptide antagonist of corticotropin-releasing factor receptor type 1, on adaptive behaviour in the rat[END_REF], and R121919 administered via minipump [START_REF] Gutman | Persistent anxiolytic affects after chronic administration of the CRF-1 receptor antagonist R121919 in rats[END_REF] or sc [START_REF] Gutman | Behavioral effects of the CRF1 receptor antagonist R121919 in rats selectively bred for high and low activity in the swim test[END_REF]. However, sc-injected R121919 increased open arm entries and duration in Wistar rats bred for high anxiety [START_REF] Keck | The anxiolytic effect of the CRH(1) receptor antagonist R121919 depends on innate emotionality in rats[END_REF].

Paradoxically, po-administered GSK876008 decreased open arm duration in rats but yet blocked the decrease caused by calcitonin gene-related peptide infused in the bed nucleus of the stria terminalis (Sink et al., 2013a).

When CRHR2 antagonists were examined, icv-administered anti-sauvagine-30 increased open arm duration in Balb/c mice [START_REF] Pelleymounter | Pharmacological evidence supporting a role for central corticotropin-releasing factor(2) receptors in behavioral, but not endocrine, response to environmental stress[END_REF] or rats [START_REF] Takahashi | Antagonism of CRF(2) receptors produces anxiolytic behavior in animal models of anxiety[END_REF] but decreased open arm entries and duration in C57BL/6J mice [START_REF] Kishimoto | Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2[END_REF]. Open arm duration also increased after icvadministered astressin in Balb/c mice [START_REF] Pelleymounter | Pharmacological evidence supporting a role for central corticotropin-releasing factor(2) receptors in behavioral, but not endocrine, response to environmental stress[END_REF]. But as with other CRHR antagonists, negative results have appeared regarding icv-administered astressin-2B and antisauvagine-30 in rats [START_REF] Zorrilla | Anxiolytic-like effects of antisauvagine-30 in mice are not mediated by CRF2 receptors[END_REF].

In general, the anxiolytic profile of CRHR antagonists appears more evident when stressors are applied prior to elevated plus-maze exposure. In particular, poadministered R278995/CRA0450 counteracted the swim stress-induced decrease in open arm time but had no effect in non-stressed rats [START_REF] Chaki | Anxiolytic-and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450[END_REF]. Moreover, icv-injected alpha-helical CRH-9-41 was effective after restraint or swim stress [START_REF] Heinrichs | Anti-stress action of a corticotropin-releasing factor antagonist on behavioral reactivity to stressors of varying type and intensity[END_REF] and ethanol withdrawal [START_REF] Baldwin | CRF antagonist reverses the "anxiogenic" response to ethanol withdrawal in the rat[END_REF], as was icvinjected alpha-helical CRH-9-41 [START_REF] Heinrichs | Corticotropin-releasing factor antagonist reduces emotionality in socially defeated rats via direct neurotropic action[END_REF][START_REF] Heinrichs | Anti-stress action of a corticotropin-releasing factor antagonist on behavioral reactivity to stressors of varying type and intensity[END_REF][START_REF] Menzaghi | Characterization of a novel and potent corticotropin-releasing factor antagonist in rats[END_REF], D-Phe-CRH-12-41 [START_REF] Menzaghi | Characterization of a novel and potent corticotropin-releasing factor antagonist in rats[END_REF], or astressin [START_REF] Spina | Behavioral effects of central administration of the novel CRF antagonist astressin in rats[END_REF] after resident intruder stress. Likewise, po-administered R121919 counteracted the reduction in open arm duration found after restraint stress [START_REF] Heinrichs | Brain penetrance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist[END_REF] and po-administered antalarmin increased open arm duration after resident intruder stress, though no such effect occurred after po-administered SSR125543A [START_REF] Griebel | (2-Chloro-4-methoxy-5methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1, 3-thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor(1) receptor antagonist. II. Characterization in rodent models of stress-related disorders[END_REF].

In line with pharmacologic data, icv-injected antisense targeting with oligodeoxynucleotides against CRH mRNA in rats subjected to resident intruder stress augmented time spent in open arms compared with sense oligodeoxynucleotide-or vehicle-treated animals [START_REF] Skutella | Corticotropin-releasing hormone (CRH) antisense oligodeoxynucleotide treatment attenuates social defeat-induced anxiety in rats[END_REF] oligodeoxynucleotide infusion did not [START_REF] Liebsch | Differential behavioural effects of chronic infusion of CRH1 and CRH2 receptor antisense oligonucleotides into the rat brain[END_REF]). Yet open arm duration paradoxically decreased in rats not subject to stress but injected icv with CRHR2 antisense oligonucleotides compared with vehicle or scrambled oligonucleotidetreated groups [START_REF] Isogawa | Anxiogenic-like effect of corticotropin-releasing factor receptor 2 antisense oligonucleotides infused into rat brain[END_REF].

In addition to pharmacological or mRNA targeting, genetic information related to CRH has been provided. As expected, Crh transgenic mice overexpressing the rat version of the gene had shorter open arm duration than non-transgenic controls, an effect reversed by icv-administered alpha-helical-CRH-9-41 [START_REF] Stenzel-Poore | Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior[END_REF]. Also as expected, null mutant mice lacking CRH binding protein (presumably increasing free CRH levels) had fewer open arm entries and shorter duration than wild-type [START_REF] Karolyi | Altered anxiety and weight gain in corticotropin-releasing hormone-binding protein-deficient mice[END_REF]). Yet Crh-deficient mouse models did not differ from wild-type in open arm exploration either with or without restraint stress [START_REF] Dunn | Behavioral responses to stress are intact in CRF-deficient mice[END_REF][START_REF] Weninger | Stress-induced behaviors require the corticotropin-releasing hormone (CRH) receptor, but not CRH[END_REF]. More in tune with expectations, Crhr1 null mutant mice deficient in CRHR1 showed an anxiolytic-like effect in the elevated plusmaze [START_REF] Contarino | Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1[END_REF]Gammie and Stevenson, 2006;[START_REF] Smith | Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development[END_REF],

though not when tested a few days after post-partum, indicating elimination of the genetic difference through lactation (Gammie et al., 2007). A tendency towards an anxiolytic response (P=0.06) occurred with conditional Crhr1 null mutant mice lacking CRHR1 in the limbic system [START_REF] Müller | Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress[END_REF]. Although Crhr2 null mutants on a hybrid 129SvJ-C57BL/6J genetic background had fewer entries and spent less time in the open arms [START_REF] Bale | Mice deficient for corticotropinreleasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress[END_REF][START_REF] Kishimoto | Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2[END_REF], no such effect occurred in another Crhr2 knockout on a purer C57BL/6J background [START_REF] Zorrilla | Anxiolytic-like effects of antisauvagine-30 in mice are not mediated by CRF2 receptors[END_REF], indicating an interaction between this gene and others.

Injections in specific brain regions

The anatomical basis of CRH-mediated anxiogesis on the elevated plus-maze has been examined at the level of the limbic system (Table 3). CRH infused in the basolateral amygdala decreased open arm entries and duration in mice, whereas infusion in the same region of the CRHR1 antagonist, CP376395, but not the CRHR2 antagonist, antisauvagine-30, increased open arm duration [START_REF] Cipriano | CRF receptor type 1 (but not type 2) located within the amygdala plays a role in the modulation of anxiety in mice exposed to the elevated plus maze[END_REF], a distinction attributable to the exceptional richness of CRHR1 in this brain region (see section 1.1). Likewise, CRH infused in the basolateral amygdala decreased open arm duration in rats (Gray et al., 2015). On the contrary, no such effect occurred in rats injected in the basolateral amygdala for five days with or without prior restraint stress, perhaps a sign of rapid tolerance [START_REF] Daniels | The effects of repeated intraamygdala CRF injections on rat behavior and HPA axis function after stress[END_REF]. When a lentiviral vector overexpressed CRH in the central nucleus of the amygdala of female rats before weaning, open arm duration decreased in peripubertal rats [START_REF] Li | Overexpression of corticotropin releasing factor in the central nucleus of the amygdala advances puberty and disrupts reproductive cycles in female rats[END_REF]. But no such effect occurred after 4-month lentivirus-induced CRH overexpression in this region in adult mice, a sign of compensation after long-length exposure [START_REF] Regev | Prolonged and site-specific over-expression of corticotropinreleasing factor reveals differential roles for extended amygdala nuclei in emotional regulation[END_REF]. In an opposite fashion to CRH administration, CRH knockdown in the central nucleus of the amygdala by a lentivirus increased open arm entries and duration after restraint stress in mice [START_REF] Regev | Site-specific genetic manipulation of amygdala corticotropin-releasing factor reveals its imperative role in mediating behavioral response to challenge[END_REF]. Likewise, CRH knockdown with RNA oligonucleotides in the central nucleus of the amygdala increased open arm entries in rats [START_REF] Callahan | Inhibition of corticotropin releasing factor expression in the central nucleus of the amygdala attenuates stress-induced behavioral and endocrine responses[END_REF]. In the case of CRHR antagonists, alpha-helical CRH-9-41 injected in the central nucleus of the amygdala counteracted the decrease in open arm time after ethanol withdrawal but not in placebo-treated rats ( [START_REF] Rassnick | Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal[END_REF]. Likewise, subchronic infusion of antisense oligodeoxynucleotides against CRHR1 mRNA in the central nucleus of the amygdala increased open arm duration after resident intruder-induced stress relative to scrambled sequence oligodeoxynucleotide-treated rats and vehicle controls [START_REF] Liebsch | Chronic infusion of a CRH1 receptor antisense oligodeoxynucleotide into the central nucleus of the amygdala reduced anxiety-related behavior in socially defeated rats[END_REF].

Aside from the amygdala, other limbic regions are implicated in CRH-mediated anxiogenesis in the elevated plus-maze. CRH injected in the ventral hippocampus decreased open arm time in rats [START_REF] Pentkowski | Effects of acidic-astressin and ovine-CRF microinfusions into the ventral hippocampus on defensive behaviors in rats[END_REF]. On the contrary, no such effect occurred following intrahippocampal injection of CRH in Balb/c mice [START_REF] Radulovic | Modulation of learning and anxiety by corticotropin releasing factor (CRF) and stress: differential roles of CRF receptors 1 and 2[END_REF]. Instead, CRH decreased open arm entries and duration after administration in the lateral septum, an effect counteracted by CRHR2 antagonists, antisauvagine-30 or astressin [START_REF] Radulovic | Modulation of learning and anxiety by corticotropin releasing factor (CRF) and stress: differential roles of CRF receptors 1 and 2[END_REF]. Likewise, the CRHR2 agonist, urocortin-1 (Bakshi et al., 2007) and the CRHR1 agonist, cortagine [START_REF] Tezval | Cortagine, a specific agonist of corticotropin-releasing factor receptor subtype 1, is anxiogenic and antidepressive in the mouse model[END_REF], decreased open arm entries and duration when injected in the lateral septum.

CRH also reduced open arm entries and duration when infused in the bed nucleus of the stria terminalis, an effect inhibited by co-infusion with CP-154,526 but not antisauvagine-30, therefore mediated by CRHR1 [START_REF] Sahuque | Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes[END_REF]. But an opposite conclusion is reached when considering that open arm time decreased after infusion of the CRHR2 antagonist, astressin-2B, in the bed nucleus of the stria terminalis, but not the CRHR1 antagonist, CP376395 [START_REF] Tran | Importance of CRF receptor-mediated mechanisms of the bed nucleus of the stria terminalis in the processing of anxiety and pain[END_REF]. In three more experiments, negative results have been obtained regarding this brain region.

Urocortin-1 administered in the bed nucleus of the stria terminalis had no effect in the elevated plus-maze [START_REF] Lee | Repeated stimulation of CRF receptors in the BNST of rats selectively induces social but not panic-like anxiety[END_REF] and neither did a lentivirus containing a CRHspecific promoter used to overexpress CRH in the bed nucleus of the stria terminalis for 14 days (Sink et al., 2013b) or 4 months [START_REF] Regev | Prolonged and site-specific over-expression of corticotropinreleasing factor reveals differential roles for extended amygdala nuclei in emotional regulation[END_REF].

In addition to the limbic system, midbrain regions are implicated in CRHmediated anxiogenesis in the elevated plus-maze. Indeed, CRH infused in the dorsal periaqueductal grey decreased open arm exploration in mice [START_REF] Borelli | Effects of ovine CRF injections into the dorsomedial, dorsolateral and lateral columns of the periaqueductal gray: a functional role for the dorsomedial column[END_REF] and rats, an anxiogenic effect blocked by injections in the same brain area of the CRHR1 antagonist NBI27914, but not the CRHR2 antagonist, anti-sauvagine-30 [START_REF] Miguel | Anxiogenic and antinociceptive effects induced by corticotropin-releasing factor (CRF) injections into the periaqueductal gray are modulated by CRF1 receptor in mice[END_REF]. Moreover, CRH injected in the dorsal periaqueductal grey potentiated the anxiogenic effect of restraint stress in rats, an effect blocked by injecting in the same brain region the non-selective CRHR antagonist, alpha-helical-CRH-9-41 [START_REF] Martins | Anxiogenic effect of corticotropin-releasing hormone in the dorsal periaqueductal grey[END_REF], which also blocked the anxiogenic effect of restraint stress alone (Martins et al., 2000). In contrast, CRH administered in the medial raphe, a region that projects 5HT fibers to dorsal hippocampus and amygdala [START_REF] Hensler | Serotonergic modulation of the limbic system[END_REF], had no impact on the elevated plusmaze (Ohnura et al., 2008).

When telencephalic regions are examined, we see that CRH injected in the shell subregion of the nucleus accumbens in rats reduced open arm duration in the elevated plus-maze [START_REF] Chen | Corticotropin-releasing factor in the nucleus accumbens shell induces swim depression, anxiety, and anhedonia along with changes in local dopamine/acetylcholine balance[END_REF]. Likewise, CRH injected in the medial

prefrontal cortex reduced open arm entries and duration in mice, whereas the CRHR1 antagonist, CP376395, had the opposite effect [START_REF] Miguel | Tonic modulation of anxiety-like behavior by corticotropin-releasing factor (CRF) type 1 receptor (CRF1) within the medial prefrontal cortex (mPFC) in male mice: role of protein kinase A (PKA)[END_REF]. CRH injected in the medial prefrontal cortex was also anxiogenic in rats, though only at a low dose, the high dose producing an anxiolytic effect [START_REF] Ohata | Microinjection of different doses of corticotropinreleasing factor into the medial prefrontal cortex produces effects opposing anxiety-related behavior in rats[END_REF].

Intra-medial prefrontal cortex infusions of CRH reduced open arm entries and duration regardless of whether rats were preexposed to restraint stress [START_REF] Jaferi | Corticotropin-releasing hormone receptors in the medial prefrontal cortex regulate hypothalamic-pituitary-adrenal activity and anxiety-related behavior regardless of prior stress experience[END_REF]. In contrast, CRH administered in the Fr2 region of rat frontal cortex increased open arm entries, an anxiolytic effect blocked by alpha-helical-CRH-9-41 and NBI27914 [START_REF] Zieba | The behavioural and electrophysiological effects of CRF in rat frontal cortex[END_REF].

Thus, under some conditions, CRH is anxiogenic in the elevated plus-maze when injected in basolateral amygdala, ventral hippocampus, lateral septum, bed nucleus of the stria terminalis, nucleus accumbens, periaqueductal grey, and medial frontal cortex, regions containing CRHR1 and CRHR2. The same effect occurred after CRH overexpression by a lentiviral vector in the central amygdala. In an opposite manner, anxiolytic effects were seen after CRH knockdown in central amygdala and CRHR antagonist injections in basolateral and central amygdala, and medial prefrontal cortex. As mentioned in section 2.2.1, the amygdala and hippocampus are interconnected and the subiculum projects to the nucleus accumbens [START_REF] Witter | Hippocampal formation[END_REF]). Basolateral and central nuclei of the amygdala project to the paraventricular hypothalamus, source of CRH-containing neurons (Gray, 1993;[START_REF] Gray | Direct projections from the central amygdaloid nucleus to the hypothalamic paraventricular nucleus: possible role in stress-induced adrenocorticotropin release[END_REF]. As mentioned in overview section 1, CRHcontaining neurons are also found in the bed nucleus of the stria terminalis, a major afferent region to the paraventricular hypothalamus. The anxiety-inducing effects of CRH in the periaqueductal grey may be explained by its afferents from amygdala, bed nucleus of the stria terminalis, and hypothalamus (Gray and Magnuson, 1992).

Moreover, the periaqueductal grey receives fibers from the medial prefrontal cortex that also innervate the hypothalamus [START_REF] Keay | Periaqueductal grey[END_REF].

Other stress-linked peptides in hypothalamus and pituitary

The icv injection of neuromedin S, an HPA activator [START_REF] Mori | Neuromedin S: discovery and functions[END_REF], decreased open arm entries and duration relative to a vehicle solution [START_REF] Jaszberenyi | Endocrine and behavioral effects of neuromedin S[END_REF]. Anxiogenic effects in the elevated plus-maze were also revealed after ip or 3 rd ventricle administration of ghrelin, an effect counteracted by the CRHR antagonist alpha-helical CRH-9-41 (Asakawa et al., 2001). Ip-injected ghrelin augmented serum corticosterone levels and hypothalamic CRH but not urocortin mRNA expression in the hypothalamus. Ghrelin decreased open arm entries and duration in rats whether injected icv [START_REF] Carlini | Ghrelin increases anxiety-like behavior and memory retention in rats[END_REF] or in hippocampus but not amygdala or dorsal raphe [START_REF] Carlini | Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin[END_REF]. The same decrease in open arm entries and duration occurred with ghrelin infused into arcuate, paraventricular, ventromedial, or perifornical region of lateral hypothalamus [START_REF] Currie | Ghrelin is an orexigenic peptide and elicits anxiety-like behaviors following administration into discrete regions of the hypothalamus[END_REF]. Icvadministered urotensin-2 also decreased open arms entries and duration in mice [START_REF] Matsumoto | Intracerebroventricular administration of urotensin II promotes anxiogenic-like behaviors in rodents[END_REF]. Likewise, icv-administered obestatin decreased open arm duration [START_REF] Szakacs | The effect of obestatin on anxiety-like behaviour in mice[END_REF], as did icv-infused PACAP, an effect counteracted by the CRHR antagonist, D-Phe-CRH-12-41 [START_REF] Dore | CRF mediates the anxiogenic and anti-rewarding, but not the anorectic effects of PACAP[END_REF]. Similarly, open arm entries were downregulated after icv-administered C-type natriuretic peptide and blocked by alpha-helical-CRH [START_REF] Jahn | Alpha-helical-corticotropin-releasing hormone reverses anxiogenic effects of C-type natriuretic peptide in rats[END_REF]. But in regard to a pituitary-like hormone, sc-administered ORG2766, the ACTH analog, in neonatal rats had no effect on open arm exploration when tested at 3 months of age [START_REF] Horvath | Early postnatal treatment with ACTH4-9 analog ORG 2766 improves adult spatial learning but does not affect behavioural stress reactivity[END_REF].

Glucocorticoid and mineralocorticoid receptor agonists and antagonists

Intracerebroventricular and peripheral injections

Corticosterone effects on the elevated plus-maze seem to fit within narrow dose ranges and lengths of treatment. Acute 5 mg/kg sc corticosterone increased open arm entries and duration in rats (Andreatini and Leite, 1994). A higher acute dose of 20 mg/kg ip corticosterone increased open arm duration in rats even when tested one week after the injection [START_REF] Wang | High-dose corticosterone after fear conditioning selectively suppresses fear renewal by reducing anxiety-like response[END_REF]. But with the same delay, a lower acute dose of 10 mg/kg sc corticosterone decreased open arm entries and duration in rats [START_REF] Kim | Regional differences in acute corticosterone-induced dendritic remodeling in the rat brain and their behavioral consequences[END_REF][START_REF] Mitra | Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy[END_REF]. The same decrease in open arm duration was found after acute 0.5 mg/kg ip corticosterone at the more usual 20 min post-injection interval in C57BL/6 mice [START_REF] Espallergues | HDAC6 regulates glucocorticoid receptor signaling in serotonin pathways with critical impact on stress resilience[END_REF]. On the contrary, no effect occurred after acute 20 or 40 mg/kg ip corticosterone in rats [START_REF] Lim | Enhancement of anxiety and modulation of TH and pERK expressions in amygdala by repeated injections of corticosterone[END_REF].

There is clearer evidence regarding corticosterone-induced anxiogenesis after repeated administration. In rats, 20 mg/kg corticosterone ip for 1, 2, or 3 weeks decreased open arm duration, as did 25 mg/kg sc corticosterone for 4 weeks [START_REF] Pego | Dissociation of the morphological correlates of stress-induced anxiety and fear[END_REF] or 40 mg/kg ip for 1 or 3 weeks [START_REF] Lim | Enhancement of anxiety and modulation of TH and pERK expressions in amygdala by repeated injections of corticosterone[END_REF]. Likewise, 40 mg/kg sc corticosterone for 3 [START_REF] Lee | Chronic administration of catechin decreases depression and anxiety-like behaviors in a rat model using chronic corticosterone injections[END_REF] or 4 [START_REF] Lee | Chronic corticosterone exposure increases expression and decreases deoxyribonucleic acid methylation of Fkbp5 in mice[END_REF] weeks decreased open arm duration in C57BL/6J mice. Moreover, a 3-week regimen of corticosterone in drinking water decreased open arm entries and duration in rats (Donner et al., 2012).

Rats chronically administered via osmotic minipumps with the mineralocorticoid agonist, aldosterone, also had fewer open arm entries and duration [START_REF] Hlavacova | Chronic treatment with the mineralocorticoid hormone aldosterone results in increased anxiety-like behavior[END_REF]. On the contrary, 10 mg/kg sc corticosterone for 10 days had no effect on the elevated plus-maze in rats [START_REF] Mitra | Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy[END_REF] and neither did a slowrelease pellet of corticosterone for 3 weeks in C57BL/6J mice (Demuyser et al., 2016). Thus, anxiogenesis seems evident at 20 mg/kg or higher for at least one week.

Two studies concern the effects of glucocorticoids during development. When mother rats were injected sc with dexamethasone thoughout pregnancy or only the final week of gestation, adult offspring had fewer total arm entries than vehicletreated rats only in the latter procedure [START_REF] Welberg | Prenatal glucocorticoid programming of brain corticosteroid receptors and corticotrophin-releasing hormone: possible implications for behaviour[END_REF]. But when mother rats were injected sc with corticosterone from postnatal days 30 to 45, offspring tested on postnatal day 46 showed no change in the elevated plus-maze, and neither did corticosterone administered in the drinking water on postnatal days 30 to 45 or 70 to 85 [START_REF] Waters | Caveats of chronic exogenous corticosterone treatments in adolescent rats and effects on anxiety-like and depressive behavior and hypothalamic-pituitary-adrenal (HPA) axis function[END_REF].

One might expect the opposite pattern of anxiolysis with glucocorticoid inhibitors or receptor antagonists, as found when acute 25 mg/kg ip metyrapone, the corticosterone synthesis inhibitor, increased open arm duration in previously footshock-stressed though not in non-stressed rats [START_REF] Roozendaal | Dose-dependent suppression of adrenocortical activity with metyrapone: effects on emotion and memory[END_REF].

Likewise, acute 75 mg/kg ip metyrapone had no effect on open arm exploration in non-stressed mice [START_REF] Lorivel | Effects of corticosterone synthesis inhibitor metyrapone on anxiety-related behaviors in Lurcher mutant mice[END_REF]). An acute icv injection of either the glucocorticoid receptor antagonist, mifepristone, or the mineralocorticoid receptor antagonist, spironolactone, prevented the decrease in open arm duration after restraint stress [START_REF] Calvo | Glucocorticoid and mineralocorticoid receptors are involved in the facilitation of anxiety-like response induced by restraint[END_REF]. Likewise, open arm duration increased after icv-injected mifepristone or spironolactone after footshock stress [START_REF] Korte | Anxiolytic-like effects of selective mineralocorticoid antagonists on fear-enhanced behavior in the elevated plus-maze[END_REF]. In addition, chronic sc treatment with the mineralocorticoid receptor antagonist, eplerenone, increased open arm entries and duration [START_REF] Hlavacova | Eplerenone, a selective mineralocorticoid receptor blocker, exerts anxiolytic effects accompanied by changes in stress hormone release[END_REF]. But continuous icv administration of mifepristone for 4 days had no effect in the elevated plus-maze in non-stressed rats [START_REF] Oitzl | Continuous blockade of brain glucocorticoid receptors facilitates spatial learning and memory in rats[END_REF].

Again in line with an anxiolytic action, transgenic mice bearing a glucocorticoid receptor antisense construct had higher open arm entries and duration than wild-type [START_REF] Rochford | Behavioral reactivity to aversive stimuli in a transgenic mouse model of impaired glucocorticoid (type II) receptor function: effects of diazepam and FG-7142[END_REF]. Moreover, viral-mediated overexpression of a chimeric steroid receptor binding glucocorticoids but transducing them to an estrogenic effect increased open arm duration in rats [START_REF] Mitra | Expression of chimeric estrogen-glucocorticoidreceptor in the amygdala reduces anxiety[END_REF]. On the contrary, rats injected icv for 1 week with an 18-base end-capped phosphorothioate-protected antisense oligodeoxynucleotide directed against mineralocorticoid receptor mRNA did not differ from controls in the elevated plus-maze [START_REF] Reul | Increased stress-induced adrenocorticotropin response after long-term intracerebroventricular treatment of rats with antisense mineralocorticoid receptor oligodeoxynucleotides[END_REF].

Injections in specific brain regions

When specific brain regions are examined (Table 4), open arm duration declined after implants in amygdala of either dexamethasone or aldosterone, agonists respectively at glucocorticoid and mineralocorticoid sites, an effect reversed by their respective antagonists, mifepristone or spironolactone [START_REF] Myers | Divergent effects of amygdala glucocorticoid and mineralocorticoid receptors in the regulation of visceral and somatic pain[END_REF]. Open arm duration also declined after corticosterone implants in the central nucleus of the amygdala, an effect mitigated by either mifepristone or spironolactone [START_REF] Myers | Corticosteroid receptormediated mechanisms in the amygdala regulate anxiety and colonic sensitivity[END_REF].

In addition, long-lasting corticosterone implants in the central nucleus of the amygdala decreased open arm entries [START_REF] Shepard | Corticosterone delivery to the amygdala increases corticotropin-releasing factor mRNA in the central amygdaloid nucleus and anxiety-like behavior[END_REF] and duration [START_REF] Greenwood-Van Meerveld | Stereotaxic delivery of corticosterone to the amygdala modulates colonic sensitivity in rats[END_REF][START_REF] Shepard | Corticosterone delivery to the amygdala increases corticotropin-releasing factor mRNA in the central amygdaloid nucleus and anxiety-like behavior[END_REF], an effect attributable to increased basal levels of CRH mRNA [START_REF] Shepard | Corticosterone delivery to the amygdala increases corticotropin-releasing factor mRNA in the central amygdaloid nucleus and anxiety-like behavior[END_REF]. Moreover, open arm entries and duration declined after implants in the central nucleus of the amygdala of another glucocorticoid receptor agonist, RU28362, in ovariectomized rats [START_REF] Weiser | Estrogen receptor beta activation prevents glucocorticoid receptor-dependent effects of the central nucleus of the amygdala on behavior and neuroendocrine function[END_REF]. In an opposite manner, viral-mediated overexpression of mineralocorticoid receptors in the basolateral amygdala increased open arm entries and duration in non-stressed rats as well as open arm entries after restraint stress [START_REF] Mitra | Mineralocorticoid receptor overexpression in basolateral amygdala reduces corticosterone secretion and anxiety[END_REF].

When intrahippocampal effects of mifepristone and spironolactone were considered, only the latter increased open arm entries and duration, an effect eliminated in adrenalectomized rats [START_REF] Bitran | Corticosterone is permissive to the anxiolytic effect that results from the blockade of hippocampal mineralocorticoid receptors[END_REF] [START_REF] Croteau | Behavioral effects of chronically elevated corticosterone in subregions of the medial prefrontal cortex[END_REF].

When brainstem regions are examined, mifepristone infused in the nucleus of the solitary tract decreased open arm entries (Ghosal et al., 2014). In an opposite manner, viral-mediated deletion of glucocorticoid receptors in the dorsal raphe increased open arm duration in non-stressed but not in mice subject to intruder stress [START_REF] Vincent | Glucocorticoid receptor deletion from the dorsal raphé nucleus of mice reduces dysphoria-like behavior and impairs hypothalamic-pituitary-adrenocortical axis feedback inhibition[END_REF].

In summary, amygdala, hippocampus, prefrontal cortex, and nucleus of the solitary tract, and dorsal raphe appear as targets for glucocorticoid-or mineralocorticoid-mediated effects on anxiety-related behavior in the elevated plusmaze. There is evidence that agonists at both receptors in the amygdala decrease open arm exploration. The mineralocorticoid receptor at least appears relevant in the hippocampus as well as the glucocorticoid receptor in the dorsal raphe and the nucleus of the solitary tract. As mentioned in sections 2.2.1 and 5.1.2, the amygdala and hippocampus are anatomically interrelated. The nucleus of the solitary tract is relevant to emotion-related phenomena because it possesses abundant glucocorticoid and mineralocorticoid receptors [START_REF] Herman | Regulation of adrenocorticosteroid receptor mRNA expression in the central nervous system[END_REF], receives input from infralimbic cortex [START_REF] Fisk | Descending projections of infralimbic cortex that mediate stimulation-evoked changes in arterial pressure[END_REF] and central amygdaloid nucleus [START_REF] Saha | Role of the central nucleus of the amygdala in the control of blood pressure: descending pathways to medullary cardiovascular nuclei[END_REF], and projects back to these regions in addition to the bed nucleus of the stria terminalis [START_REF] Saper | Central autonomic system[END_REF]. Widespread ascending dorsal raphe target areas include hypothalamus, basal ganglia, and neocortex [START_REF] Harding | The serotonin and tachykinin systems[END_REF].

Elevated T-maze

The elevated T-maze consists of one arm surrounded by three walls intersecting two open arms (Graeff et al., 1998;[START_REF] Pinheiro | Elevated mazes as animal models of anxiety: effects of serotonergic agents[END_REF][START_REF] Zangrossi | Serotonin in anxiety and panic: contributions of the elevated T-maze[END_REF]. Emergence latencies from the enclosed arm reflect anxiety-like behavior, whereas escape latencies from an open arm reflect panic-like behavior. As in the elevated plus-maze (see section 5), diazepam is an effective anxiolytic in the elevated T-maze [START_REF] Echeverry | Comparison of neurokinin SP with diazepam in effects on memory and fear parameters in the elevated T-maze free exploration paradigm[END_REF][START_REF] Viana | The elevated T-maze: a new animal model of anxiety and memory[END_REF].

CRHR agonists and antagonists

The anatomic basis of elevated T-maze behavior has only just begun to be mapped out (Table 5). CRH injected in the medial nucleus of the amygdala increased latencies before rats emerged from the enclosed arm of the elevated T-maze, whereas injection in the same brain area of the CRHR1 antagonist, antalarmin, counteracted the anxiogenic effects of CRH and at a higher dose decreased these latencies [START_REF] Vicentini | CRF type 1 receptors of the medial amygdala modulate inhibitory avoidance responses in the elevated T-maze[END_REF]. Likewise, the CRHR2 agonist, urocortin-2, injected in the medial nucleus of the amygdala increased latencies before rats emerged from the enclosed arm, whereas intra-amygdala astressin 2-B, a CRHR2 antagonist, counteracted the anxiogenic effects of urocortin-2 and at a higher dose decreased these latencies (Alves et al., 2016).

In addition to the amygdala, CRH injected in the dorsomedial hypothalamus, a region involved in the cardiovascular responses to stress [START_REF] Stotz-Potter | Muscimol acts in dorsomedial but not paraventricular hypothalamic nucleus to suppress cardiovascular effects of stress[END_REF], increased latencies before emerging from the enclosed arm, whereas antalarmin counteracted the anxiogenic effects of CRH and at a higher dose decreased these latencies (Silva et al., 2014). However, when injected into the periaqueductal gray, CRH facilitated escape not avoidance responses, a panicogenic effect, whereas urocortin-2 caused the reverse effect [START_REF] Sergio | Effects of dorsal periaqueductal gray CRF1-and CRF2-receptor stimulation in animal models of panic[END_REF]. These results indicate that although CRH has anxiogenic properties in amygdala and dorsomedial hypothalamus, it may also cause panic-like responses in the periaqueductal gray.

Glucocorticoids and mineralocorticoids

Corticosterone administration in the drinking water for 21 days increased avoidance latencies without affecting escape latencies in the elevated T-maze [START_REF] Fan | Corticosterone administration up-regulated expression of norepinephrine transporter and dopamine β-hydroxylase in rat locus coeruleus and its terminal regions[END_REF]. Likewise, a slow-release corticosterone pellet for 21 days increased avoidance latencies without affecting escape latencies (Diniz et al., 2011).

Unexpectedly, the glucocorticoid receptor antagonist, mifepristone, or the mineralocorticoid receptor antagonist, spironolactone, injected sc for 21 days also increased avoidance latencies without affecting escape latencies [START_REF] Fan | Corticosterone administration up-regulated expression of norepinephrine transporter and dopamine β-hydroxylase in rat locus coeruleus and its terminal regions[END_REF].

Emergence from a small compartment and defensive withdrawal

In emergence and defensive withdrawal tests, a small compartment is inserted inside a larger one. In the emergence test, animals are placed inside the small compartment and the time taken before emerging with four paws towards the larger one is measured [START_REF] Lalonde | Relations between open-field, elevated plusmaze, and emergence tests as displayed by C57BL/6J and BALB/c mice[END_REF][START_REF] Paré | The emergence test: effects of psychotropic drugs on neophobic disposition in Wistar Kyoto (WKY) and Sprague Dawley rats[END_REF]. The emergence test is over as soon as the animal exits the small compartment. Each compartment may be either familiar or novel to the animal. The smaller compartment may be its home-cage with cage-mates removed. In the defensive withdrawal test, beside emergence latencies, entries and time spent in each compartment are measured.

The defensive withdrawal test continues until a specific cut-off time is reached while the animal re-enters and vacates each compartment at will.

Relative to the non-stress condition, restraint stress increased latencies before emerging from the small chamber as well as the time spent in it [START_REF] Smagin | Corticotropin-releasing factor receptor antagonist infused into the locus coeruleus attenuates immobilization stress-induced defensive withdrawal in rats[END_REF].

In an opposite manner, chlordiazepoxide decreased emergence latencies and time spent in the small compartment [START_REF] He | 4-(1,3-dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)pyrazolo[1,5-a]1,3,5-triazine : a potent, orally bioavailable CRF1 receptor antagonist[END_REF][START_REF] Lalonde | Relations between open-field, elevated plusmaze, and emergence tests in C57BL/6J and BALB/c mice injected with GABAand 5HT-anxiolytic agents[END_REF]Yang et al., 1990). Likewise, diazepam [START_REF] Paré | The emergence test: effects of psychotropic drugs on neophobic disposition in Wistar Kyoto (WKY) and Sprague Dawley rats[END_REF] and alprazolam [START_REF] Lelas | Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats[END_REF] reduced emergence latencies from the small chamber.

CRHR agonists and antagonists

Intracerebroventricular and peripheral injections

In contrast to benzodiazepines, icv-administered CRH increased emergence latencies as well as exits from and time spent inside the small compartment [START_REF] Spina | Time-dependent induction of anxiogenic-like effects after central infusion of urocortin or corticotropin-releasing factor in the rat[END_REF][START_REF] Ward | Corticotropin-releasing factor and defensive withdrawal: inhibition of monoamine oxidase prevents habituation to chronic stress[END_REF]Yang and Dunn, 1990;Yang et al., 1990). As expected from the poor brain penetration of CRH, emergence latencies increased only after icv, not ip, injections [START_REF] Takahashi | Corticotropin-releasing factor modulates defensive-withdrawal and exploratory behavior in rats[END_REF]. No such anxiogenic action occurred after icv-injected urocortin-1, the CRHR2 agonist [START_REF] Spina | Time-dependent induction of anxiogenic-like effects after central infusion of urocortin or corticotropin-releasing factor in the rat[END_REF]. An expected finding is that Crhbp null mutant mice lacking CRH binding protein had fewer exits from the small to the large chamber and did not differ in latencies to first exit [START_REF] Karolyi | Altered anxiety and weight gain in corticotropin-releasing hormone-binding protein-deficient mice[END_REF].

In an opposite manner to CRH, anxiolytic-like effects have been obtained with CRHR antagonists. In particular, emergence latencies decreased after icv-injected alpha-helical-CRH-9-41 [START_REF] Takahashi | Corticotropin-releasing factor modulates defensive-withdrawal and exploratory behavior in rats[END_REF]. This treatment reduced both emergence latencies and time spent in the small compartment (Rodriguez de [START_REF] Rodriguez De Fonseca | Corticotropin-releasing factor (CRF) antagonist [D-Phe 12, NLE21,38, CalphaMeLeu37] CRF attenuates the acute actions of the highly potent cannabinoid receptor agonist HU-210 on defensive-withdrawal behavior in rats[END_REF] as well as reversing restraint stress-induced increases in emergence latencies and time spent in the small compartment (Yang et al., 1990).

The same pattern was discerned with selective CRHR1 antagonists, since ip-injected antalarmin decreased emergence latencies and time spent in the small compartment [START_REF] Zorrilla | Effects of antalarmin, a CRF type 1 receptor antagonist, on anxiety-like behavior and motor activation in the rat[END_REF] and chronic treatment with the same drug via osmotic minipumps increased time spent in the large compartment (Arborelius et al., 2000).

Moreover, po-administered DMP904 reduced emergence latencies [START_REF] He | 4-(1,3-dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)pyrazolo[1,5-a]1,3,5-triazine : a potent, orally bioavailable CRF1 receptor antagonist[END_REF][START_REF] Lelas | Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats[END_REF] while po-administered R121919 reduced emergence latencies and time spent in the small chamber [START_REF] Heinrichs | Brain penetrance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist[END_REF]. In another study, R121919 administered via osmotic minipumps increased time spent in the large compartment but without affecting emergence latencies [START_REF] Gutman | Persistent anxiolytic affects after chronic administration of the CRF-1 receptor antagonist R121919 in rats[END_REF]. Concordant with the anxiolytic-like pattern of CRHR1 blockade is the finding that Crhr1 null mutant mice emerged more quickly compared with wild-type and spent a longer time outside the small compartment [START_REF] Smith | Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development[END_REF]. In addition, chronic icv-administered antisense CRHR1 but not CRHR2 oligonucleotides decreased emergence latencies and time spent in the small compartment [START_REF] Heinrichs | Corticotropin-releasing factor CRF1, but not CRF2, receptors mediate anxiogenic-like behavior[END_REF]). Yet the influence of CRHR2 cannot yet be excluded, because time spent in the large compartment increased after icv administration of the CRHR2 antagonist, anti-sauvagine-30 [START_REF] Takahashi | Antagonism of CRF(2) receptors produces anxiolytic behavior in animal models of anxiety[END_REF].

Injections in specific brain regions

The anatomical basis of CRH-mediated effects on emergence and defensive withdrawal tests has rarely been examined (Table 6). A lentivirus containing a CRHspecific promoter used to overexpress CRH in the bed nucleus of the stria terminalis for 14 days had no effect (Sink et al., 2013b). However, time spent inside the small chamber of the defensive withdrawal test increased when CRH was injected in the locus coeruleus [START_REF] Butler | Corticotropinreleasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus[END_REF]. In an opposite manner, alpha-helical CRH-9-41 infusion in the locus coeruleus prior to restraint stress decreased time spent in the small chamber [START_REF] Smagin | Corticotropin-releasing factor receptor antagonist infused into the locus coeruleus attenuates immobilization stress-induced defensive withdrawal in rats[END_REF]. Arborelius et al. (2000) hypothesized that CRH neurons in Barrington's nucleus that project to the locus coeruleus (Aston- Jones, 2004;[START_REF] Valentino | Evidence for divergent projections to the brain noradrenergic system and the spinal parasympathetic system from Barrington's nucleus[END_REF] are responsible for opposing effects of CRHR agonists and antagonists on anxiety. Conversely, noradrenergic afferents may contact CRHcontaining neurons in several forebrain structures (Gray, 1993). As proposed by [START_REF] Stone | The role of the central noradrenergic system in behavioral inhibition[END_REF], the ventral noradrenergic bundle includes afferents from the lateral tegmental noradrenergic nuclei (A1 and A2) to CRH-containing neurons in paraventricular hypothalamus, bed nucleus of the stria terminalis, and central nucleus of the amygdala and may activate these neurons by stimulating α1-or βadrenoceptors.

Glucocorticoids and mineralocorticoids

Corticosterone administration in the drinking water for 17 days increased emergence latencies from the small compartment, though no effect occured after 1 day (Ardayfio and Kim, 2006).

Light-dark box

In the light-dark box test, entries and duration as well as latencies before first entry in the lit compartment reflect photophobic tendencies of nocturnal animals [START_REF] Crawley | Neuropharmacologic specificity of a simple animal model for the behavioral actions of benzodiazepines[END_REF][START_REF] Hascoët | The mouse light-dark paradigm: a review[END_REF][START_REF] Misslin | Behavioural validation of a light/dark choice procedure for testing anti-anxiety agents[END_REF]. As in other anxiety tests, diazepam has an anxiolytic action in the light-dark box test, as demonstrated by increases in time spent inside the lit compartment [START_REF] Bhatt | Anxiolytic-like effect of Nn-butyl-3-methoxyquinoxaline-2-carboxamide (60) in experimental mouse models of anxiety[END_REF][START_REF] Crawley | Neuropharmacologic specificity of a simple animal model for the behavioral actions of benzodiazepines[END_REF][START_REF] Onaivi | Neuropharmacological and physiological validation of a computer-controlled two-compartment black and white box for the assessment of anxiety[END_REF]. As in other anxiety tests, mouse strain differences have been noted [START_REF] Kulesskaya | Assessment of mouse anxiety-like behavior in the light-dark box and open-field arena: role of equipment and procedure[END_REF].

CRH receptor agonists and antagonists

Unlike diazepam, icv-administered urocortin-1 reduced entries and duration in the lit part of the light-dark box in mice [START_REF] Moreau | Urocortin, a novel neuropeptide with anxiogenic-like properties[END_REF]. The limbic system appears important in this test, because lentivirus-mediated CRH overexpression in the central nucleus amygdala of mice after 3-day induction by doxycycline in the drinking water decreased entries in the lit chamber following restraint stress [START_REF] Regev | Site-specific genetic manipulation of amygdala corticotropin-releasing factor reveals its imperative role in mediating behavioral response to challenge[END_REF]. However, the same manipulation after 4-month administration increased entries in the lit zone with or without restraint stress as well as increasing time spent in the lit zone after restraint stress, an overcompensatory response whose mechanism remains to be determined [START_REF] Regev | Prolonged and site-specific over-expression of corticotropinreleasing factor reveals differential roles for extended amygdala nuclei in emotional regulation[END_REF]. No effect occurred in the bed nucleus of the stria terminalis. As expected from genetic manipulations in other paradigms, Crh transgenic mice overexpressing the rat version of the gene had higher latencies before entering and spent less time in the lit portion of the box [START_REF] Van Gaalen | Effects of transgenic overproduction of CRH on anxiety-like behaviour[END_REF]. Likewise, conditional Crh transgenic mice overexpressing the rat version of the gene in neocortex and hippocampus but not hypothalamus had fewer entries in the lit portion [START_REF] Vicentini | Transient forebrain over-expression of CRF induces plasma corticosterone and mild behavioural changes in adult conditional CRF transgenic mice[END_REF].

Neither ip-injected SSR125543A nor antalarmin, CRHR1 antagonists, had any effect on mouse behavior in the light-dark box [START_REF] Griebel | (2-Chloro-4-methoxy-5methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1, 3-thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor(1) receptor antagonist. II. Characterization in rodent models of stress-related disorders[END_REF]. But, as expected, Crhr1 null mutant mice lacking CRHR1 had more entries, longer durations, and shorter latencies to enter the lit compartment [START_REF] Timpl | Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1[END_REF], as did conditional Crhr1 null mutant mice lacking CRHR1 specifically in the limbic system [START_REF] Müller | Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress[END_REF]. The basal ganglia also appears involved because knockdown of CRHR1 mRNA by a lentiviral-based system in the mouse lateral globus pallidus decreased entries and time spent in the lit zone [START_REF] Sztainberg | An anxiolytic role for CRF receptor type 1 in the globus pallidus[END_REF].

Results are mixed regarding CRHR2. Indeed, icv-administered urocortin-3, the CRHR2 agonist, decreased latencies before first entry in the lit area, an anxiolytic effect [START_REF] Venihaki | Urocortin III, a brain neuropeptide of the corticotropin-releasing hormone family: modulation by stress and attenuation of some anxiety-like behaviours[END_REF]. In contrast, entries and duration in the lit chamber decreased after icv-administered CRHR2 antisense oligonucleotides compared with vehicle-or scrambled oligonucleotide-treated groups [START_REF] Isogawa | Anxiogenic-like effect of corticotropin-releasing factor receptor 2 antisense oligonucleotides infused into rat brain[END_REF]. Although one Crhr2 null mutant model showed less time spent in the lit part [START_REF] Kishimoto | Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2[END_REF], no effect occurred with a different Crhr2 null mutant model [START_REF] Bale | Mice deficient for corticotropinreleasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress[END_REF].

Glucocorticoids and mineralocorticoids

Long-lasting corticosterone implants for 4 to 16 days reduced time spent in the lit chamber, but acute 40 mg/kg ip corticosterone had no effect [START_REF] Murray | Chronic low dose corti-costerone exposure decreased hippocampal cell proliferation, volume and induced anxiety and depression like behaviours in mice[END_REF].

However, icv-injected urotensin-2 reduced entries in the lit chamber [START_REF] Do-Rego | Behavioral effects of urotensin-II centrally administered in mice[END_REF]. The limbic system appears involved, because intrahippocampal injections of sprironolactone, the mineralocorticoid receptor antagonist, increased time spent in the lit chamber [START_REF] Smythe | Hippocampal mineralocorticoid, but not glucocorticoid, receptors modulate anxiety-like behavior in rats[END_REF].

Brain regions and CRH-mediated anxiety

Elevated plus-maze and elevated T-maze tests

The anatomic basis of CRH-mediated anxiety has advanced in regard to elevated plus-maze and elevated T-maze tests (Tables 3 and5). In the elevated plus-maze, CRH caused anxiogenesis when infused in basolateral amygdala, ventral hippocampus, lateral septum, bed nucleus of the stria terminalis, nucleus accumbens, periaqueductal grey, and medial frontal cortex. Moreover, a lentiviral vector overexpressing CRH in the central nucleus of the amygdala was anxiogenic in the same maze. In the elevated T-maze, CRH was anxiogenic when infused in amygdala and dorsomedial hypothalamus. Thus, the amygdala appears as a common target of CRH-induced anxiogenesis in both tests. Further research must identify the precise neural circuits underlying both tests.

Elevated plus-maze and open-field tests

The anatomic basis of CRH-mediated anxiety has advanced in regard to elevated plus-maze and open-field tests (Tables 2 and5). In the center zone of the open-field, CRH caused anxiogenesis when infused in hippocampus and shell region of the nucleus accumbens. In an opposite manner, chronic lentivirus-induced CRH overexpression in the central nucleus of the amygdala increased center region entries, a sign of anxiolysis, which may have been the result of receptor hyposensitivity. Decreases in center zone entries and duration occurred after infusion of a CHRHR2 agonist in the lateral septum but increases in center zone entries occurred after infusion of a CRHR1 antagonist in the lateral globus pallidus.

When considering that anxiogenesis occurred after CRH infusion in basolateral amygdala, ventral hippocampus, lateral septum, bed nucleus of the stria terminalis, nucleus accumbens, periaqueductal grey, and medial frontal cortex in the elevated plus-maze, the hippocampus and nucleus accumbens appear as common targets of CRH-induced anxiogenesis in both tests. Because the subiculum projects to the nucleus accumbens [START_REF] Witter | Hippocampal formation[END_REF], these two regions may form part of the the neural circuits underlying both tests. One can see the work remaining to be done in understanding neuroanatomical pathways of exploratory activity when more than one test is considered.

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1

  Université de Rouen, Dépt Psychologie, Laboratoire ICONES EA 4699, 76821

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Figure legend Figure 1

 legend1 Figure legend

Appenrodt, E., Kröning, G., and Schwarzberg, H. (1999). Increased plasma ACTH in rats exposed to the elevated plus-maze is independent of the pineal gland.

Psychoneuroendocrinology 24, 833-838. Arborelius, L., Skelton, K.H., Thrivikraman, K.V., Plotsky, P.M., Schulz, D.W., and Owens, M.J. (2000). Chronic administration of the selective corticotropinreleasing factor 1 receptor antagonist CP-154,526: behavioral, endocrine and neurochemical effects in the rat. J. Pharmacol. Exp. Ther. 294, 588-597. Ardayfio, P. and Kim, K. (2006). Anxiogenic-like effect of chronic corticosterone in the light-dark emergence task in mice. Behav. Neurosci. 120, 249-256. Not in text Asakawa, A., Inui, A., Kaga, T., Yuzuriha, H., Nagata, T., Fujimiya, M., Katsuura, G., Makino, S., Fujino, M.A., and Kasuga, M. (2001) Skorzewska, A., Bidzinski, A., Lehner, M., Turzynska, D., Sobolewska, A., Wislowska-Stanek, A., Maciejak, P., Szyndler, J., and Plaznik, A. (2011). The localization of brain sites of anxiogenic-like effects of urocortin-2. Neuropeptides 45, 83-92.

regions known to influence the stress response (structures in grey boxes). ACTH: adrenocorticotropin hormone.