Caroline Correia

Pascal Romieu

Mary C Olmstead

Katia Befort
email: katia.befort@unistra.fr

Can cocaine-induced neuroinflammation explain maladaptive cocaine-associated memories?

Keywords: memory TLRs: Toll-like receptor TNFR: TNF receptor TNFα: tumor necrosis factor α TRAM: TRIF-related adaptor molecule TRIF: Toll interleukin receptor-domain-containing adapter-inducing interferon-β Cocaine, addiction, neuroinflammation, reconsolidation, memory

published or not. The documents may come

Can cocaine-induced neuroinflammation explain

maladaptive cocaine-associated memories?

Introduction

Drug addiction is a worldwide health problem and a primary risk factor for a variety of medical conditions. For example, cocaine use increases the risk of myocardial infarction by 24 times, and induces convulsions in 1 to 10% of users. Cocaine abuse is comorbid with other psychiatric disorders, with 24% of cocaine users reporting an anxiety disorder (OFDT, 2012). Among addictive drugs, cocaine is the most commonly consumed illicit psychostimulant in the world: 18 million people worldwide have used cocaine, among which approximately 400 000 have a cocaine use disorder (World Drug Report, 2018). The powerful reinforcing properties of cocaine lead to escalation of intake and loss of control over consumption, producing compulsive drug seeking and drug taking despite obvious negative consequences.

Importantly, cocaine abuse is characterized by a high vulnerability to chronic relapse [START_REF] Koob | Neurobiology of addiction: a neurocircuitry analysis[END_REF], which explains its resistance to treatment and perpetuation of maladaptive behavior.

Cocaine, like others drugs of abuse, directly or indirectly impacts the mesocorticolimbic pathway, leading to enhancement of dopamine (DA) neurotransmission from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) [START_REF] Di Chiara | Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats[END_REF]. This "reward pathway" mediates the reinforcing effects of natural reinforcers that have evolutionary significance (e.g., food, mating). The critical role of DA in this pathway may involve one or more processes, such as associative learning [START_REF] Corbit | Learning and Motivational Processes Contributing to Pavlovian-Instrumental Transfer and Their Neural Bases: Dopamine and Beyond[END_REF], error prediction (i.e., relationship between expected and actual outcomes) [START_REF] Schultz | Dopamine reward prediction error coding[END_REF], and motivation [START_REF] Salamone | Mesolimbic Dopamine and the Regulation of Motivated Behavior[END_REF]. Regardless of the precise process, there is general agreement that drugs of abuse, such as cocaine, hijack this system, increasing DA neurotransmission that results in strengthened reinforcement [START_REF] Chen | Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA[END_REF][START_REF] Bamford | Dopamine's Effects on Corticostriatal Synapses during Reward-Based Behaviors[END_REF].

The reinforcing effect of cocaine depends on both instrumental and classical conditioning. The former occurs as individuals learn the relationship between drug intake and drug effects, including the consequences of drug administration on alleviating withdrawal (for a discussion on the relative contributions of positive versus negative reinforcement in addiction, see review [START_REF] Wise | The development and maintenance of drug addiction[END_REF]; the latter when environmental cues become associated with drug intake [START_REF] Wikler | Classical conditioning of a morphine abstinence phenomenon, reinforcement of opioid-drinking behavior and "relapse" in morphine-addicted rats[END_REF][START_REF] Tiffany | A cognitive model of drug urges and drug-use behavior: role of automatic and nonautomatic processes[END_REF]. With classical conditioning, drug-paired cues acquire characteristics predicting drug availability, including DA release in the striatum [START_REF] Ito | Dopamine release in the dorsal striatum during cocaine-seeking behavior under the control of a drug-associated cue[END_REF]. In rodents, these conditioned cues, previously associated with cocaine consumption, can then become conditioned reinforcers and induce drug-seeking behavior, even after a long period of abstinence [START_REF] Grimm | Neuroadaptation. Incubation of cocaine craving after withdrawal[END_REF]. Enhanced drug-seeking can be observed even when animals have to override aversive stimuli such as electric shock [START_REF] Saunders | Cue-evoked cocaine "craving": role of dopamine in the accumbens core[END_REF]. Unfortunately, no effective treatments have been found to efficiently reduce rates of relapse, and it has been hypothesized that an association between environmental cues and pharmacological effects of cocaine, strongly anchored in memory, is part of the problem [START_REF] Hyman | Neural mechanisms of addiction: the role of reward-related learning and memory[END_REF]. This has stimulated a new direction in addiction research, targeting memory processes, particularly when they are reactivated, in order to weaken memories associated with cocaine and, thereby, decrease the risk of relapse (Torregrossa & Taylor, 2016).

In that respect, neuroinflammation may be an interesting target as numerous studies have linked neuroinflammatory markers to memory processes (see review [START_REF] Bader | Mitochondria at the interface between neurodegeneration and neuroinflammation[END_REF]. In addition, both human and animal studies reveal an association between chronic cocaine consumption and the upregulation of several neuroinflammatoy markers (see review [START_REF] Clark | Psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection[END_REF]. The present review aims to discuss the hypothesis that cocaine addiction results, at least in part, from an involvement of traditionnal neuroinflammatory pathways in memory processes. We summarize evidence that neuroinflammatory cytokines have a dual function in memory, and that cocaine intake can increase release of these cytokines. Finally, we propose that altered memory processes observed in cocaine addiction may result from neuroinflammatory mechanisms.

Memory

Memory: general process

Memory is the mental process of acquiring, retaining and retrieving information. It is critical for cognitive processes, such as language, decision making, and spatial navigation. Memory is a time-dependent process with three phases: encoding, storage, and retrieval. [START_REF] Gold | A Single-trace, Two Process View of Memory Storage Process[END_REF] single-trace theory hypothesized that each new event triggers a short-term memory (STM), which either fades or is encoded and stored in long-term memory (LTM) through an active process. Whether a memory moves into LTM or not depends on factors such as repetition and the attentional state of the individual. The idea that memory storage is an active process was established by several pioneering studies demonstrating that memory retention could be disrupted after post-learning manipulations (e.g., electroconvulsion or protein synthesis inhibition) [START_REF] Grecksch | Two sensitive periods for the amnesic effect of anisomycin[END_REF]. This active process allows a labile memory trace to transition to a stable and fixed form. Following this initial work, Misain and co-workers (1968) showed that old memories that are retrieved could also be disrupted by a post-reactivation manipulation (e.g., electroconvulsion). This study introduced the idea that memory may always be in one of two forms: active memory describes newly acquired memories as well as older, reactivated memories, whereas inactive memory corresponds to stored memories [START_REF] Lewis | Psychobiology of active and inactive memory[END_REF]. In other words, the process by which memory is retained in LTM indefinitely is not passive; rather, this is a flexible process within which memory can be modified and updated over time.

Consolidation and reconsolidation

The consolidation/reconsolidation theory emerged to describe the two processes in which memory switches from active to inactive forms [START_REF] Lewis | Psychobiology of active and inactive memory[END_REF]. Consolidation corresponds to the storage of a new memory whereas reconsolidation corresponds to the storage of a reactivated memory (i.e., previously-aquired memories that are retrieved). Some of the earliest studies on memory consolidation highlighted a time and protein synthesis dependent mechanism. Indeed, increasing the delay between memory formation and a subsequent manipulation produced a predictable degragation of amnesia: memory was impaired when a disruption was induced up to 6 hours after learning [START_REF] Kopp | Long temporal gradient of retrograde amnesia for a well-discriminated stimulus[END_REF]. A protein synthesis dependent mechanism of consolidation was revealed in 1968, with evidence that cycloheximide (a protein synthesis inhibitor) induces memory impairement when administered 3 hours after learning [START_REF] Barondes | Memory impairment after subcutaneous injection of acetoxycycloheximide[END_REF], suggesting that the manipulation did not impact STM, but altered memory retention through LTM. In another study, protein synthesis inhibition disturbed avoidance conditioning when it was administered 10 min prior to or 80, 240 and 360 min after training, but not when administered 45 and 165 min after training [START_REF] Grecksch | Two sensitive periods for the amnesic effect of anisomycin[END_REF]. This suggested that there are two phases of memory that are dependent on protein synthesis. Taken together, these results support the consolidation theory by showing that memory can be modified during a period following its formation and is then sustained by de novo protein synthesis.

In addition to consolidation processes, memory reactivation by retrieval also leads to a period of instability (a few hours) in which memory is labile (Misain et al., 1968).

Reconsolidation is necessary to restabilize the memory into an inactive form so that it may be stored and maintained across time. Reconsolidation provides a mechanism for updating memories over time, a process that provides an evolutionary advantage to organisms by facilitating behavioural flexibility.

After a twenty-year hiatus, Nader and co-workers (2000) revived research on consolidation and reconsolidation using a fear conditioning paradigm. In simple consolidation experiments, rats experience a tone (conditioned stimulus, CS) followed by a shock (unconditioned stimulus, US); the next day, they freeze in response to the tone. Administration of a protein synthesis inhibitor (anisomycin) up to 3 hours following the CS-US pairing, prevents the freezing response to the CS on the next day. Nader and colleagues extended this principle to reconsolidation showing that protein synthesis inhibition also disrupts post-retrieval modification of the CS-US association; administration of anisomycin following CS-induced freezing eliminates conditioned responses on a subsequent test day. In other words, memory of the CS-US association is altered following its retrieval, verifying that reconsolidation is an active process during which previously-acquired memories are labile. This process appears to be shared by many species [START_REF] Nader | A single standard for memory: the case for reconsolidation[END_REF] and is associated with specific neural sites in the mammalian brain, such as the amygdala or nucleus accumbens [START_REF] Nader | Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval[END_REF][START_REF] Fuchs | Basolateral amygdala involvement in memory reconsolidation processes that facilitate drug context-induced cocaine seeking[END_REF][START_REF] Sanchez | Reconsolidation of a cocaine-associated stimulus requires amygdalar protein kinase A[END_REF][START_REF] Théberge | The basolateral amygdala and nucleus accumbens core mediate dissociable aspects of drug memory reconsolidation[END_REF][START_REF] Arguello | Involvement of amygdalar protein kinase A, but not calcium/calmodulin-dependent protein kinase II, in the reconsolidation of cocaine-related contextual memories in rats[END_REF]. A consolidation/reconsolidation description of memory is supported by evidence that both processes involve molecular and cellular mechanisms that underlie synaptic plasticity, such as long-term potentiation (LTP) [START_REF] Lynch | Long-term potentiation and memory[END_REF]. LTP is a cellular mechanism characterized by an increase in post-synaptic neuronal responses after brief high-frequency stimulation [START_REF] Nicoll | A Brief History of Long-Term Potentiation[END_REF]. It is considered one of the cellular bases underlying learning and memory, particularly as it matches Hebbian learning rules. LTP is described as a two-phase process, i.e., early-LTP and late-LTP, corresponding to induction and maintenance in which synaptic modifications occur through de novo protein synthesis (see review [START_REF] Baltaci | Molecular Mechanisms of Early and Late LTP[END_REF]. Importantly, a two-phase process is also found in consolidation research [START_REF] Grecksch | Two sensitive periods for the amnesic effect of anisomycin[END_REF].

Integration and state-dependency

Despite the fact that the consolidation hypothesis is accepted by a large part of the scientific community, some authors have proposed that state-dependency and integration, at least to some degree, could explain the findings of consolidation experiments (Gisquet-Verrier and Riccio, 2019). This alternative hypothesis developed from studies using a passive avoidance paradigm, in which memory impairments induced by cycloheximide were reversed if subjects were presented with a reminder of the original memory [START_REF] Quartermain | Amnesia produced by electroconvulsive shock or cycloheximide: conditions for recovery[END_REF]. In further work [START_REF] Gisquet-Verrier | Integration of New Information with Active Memory Accounts for Retrograde Amnesia: A Challenge to the Consolidation/Reconsolidation Hypothesis?[END_REF], administration of cycloheximide (i.e., protein synthesis inhibitor) following a single session of an inhibitory avoidance task induced amnesia in a later retention test. Importanty, this amnesia was reversed by another cycloheximide injection 30 min prior to the retention test. The same effect was observed with manipulations following memory retrieval, confirming that the original memory was not erased, but still accessible when appropriate cues were provided on the retention test. According to the authors, these effects confirm that an amnesic effect induced by protein synthesis inhibition was induced by a retrieval impairment rather than disruption of memory storage. State-dependency and integration theories consider that the animal's internal state acts as a CS during memory formation. As such, memory recall is inhibited when the internal state of the animal does not match the internal state during memory acquisition. This theory argues that memory is active for a short period of time, during which both internal and external cues will be integrated into this memory in a protein synthesis independent manner (Gisquet-Verrier and Riccio, 2019). Despite the appeal, state dependence and integration theories of memories can not explain all instances of memory consolidation. This includes rare instances of enhanced memory [START_REF] Lee | D-cycloserine potentiates the reconsolidation of cocaine-associated memories[END_REF][START_REF] Stringfield | Role of glucocorticoid receptor-mediated mechanisms in cocaine memory enhancement[END_REF] and memory impairments when treatments are given beyond the "integration period" [START_REF] Grecksch | Two sensitive periods for the amnesic effect of anisomycin[END_REF][START_REF] Monsey | The Naturally Occurring Compound Garcinia Indica Selectively Impairs the Reconsolidation of a Cocaine-Associated Memory[END_REF].

In sum, researchers generally agree on the involvement of an active mechanism underlying memory storage, but this phenomenon is explained by different theories. This review does not address the validity of either proposal, but supports the idea that both phenomena could account for memory formation. The remainder of the review will focus on consolidation and reconsolidation as these are more plausible accounts for memory formation of drug-associated environmental cues.

Cocaine and reconsolidation

Theory of reconsolidation for cocaine addiction

Some psychiatric disorders, such as posttraumatic stress (PTSD) and addiction, are characterized by aberrant and persistent memories. In both cases, strong memories are closely linked to the development of these disorders and to the continuation of associated maladaptive behaviors [START_REF] Dunbar | Garcinol Blocks the Reconsolidation of Multiple Cocaine-Paired Cues after a Single Cocaine-Reactivation Session[END_REF]Monfils and Holms, 2018). CS-US associations become abnormally strong and result in chronic anxiety and fear (e.g., PTSD) or in the persistence of drug intake despite negative consequences (e.g., addiction). As with other drugs of abuse, cocaine addiction is characterized by a high vulnerability to relapse, even after prolonged periods of abstinence.

One of the triggers of relapse in humans is exposure to conditioned cues previously associated with cocaine consumption, a phenomenon that can be modeled in rodents using a reinstatement paradigm [START_REF] Shaham | The reinstatement model of drug relapse: history, methodology and major findings[END_REF]. In this paradigm, animals acquire drug self-administration (SA) or learn to associate a specific location with drug effects (conditioned place preference, CPP). Responses are then extinguished during a withdrawal period. Reinstatment of the drug-seeking response (lever pressing or time spent in the drug-paired compartment) is traditionnaly induced by exposure to an acute priming injection of drug, drug-associated cues, or environmental stressors. In the early 2000s, the reinstatement paradigm was incorporated into reconsolidation studies to highlight the relationship between specific memory processes and relapse-like behavior (i.e., reinstatement) [START_REF] Lee | Cue-induced cocaine seeking and relapse are reduced by disruption of drug memory reconsolidation[END_REF]; see review [START_REF] Sorg | Reconsolidation of drug memories[END_REF]. These studies were designed to decipher mechanisms involved in the memory of drug-cue associations. Behavioral protocols of these studies are based on the same sequence of phases as reconsolidation studies using fear conditioning: learning, extinction, reactivation (induced by cues, context, or cocaine) followed by a memory manipulation assay, and reinstatement. Drug reinstatement studies suggested that manipulating reconsolidation of cocaineassociated memories is a potential therapeutic strategy to reduce relapse [START_REF] Rich | Molecular and synaptic mechanisms regulating drug-associated memories: Towards a bidirectional treatment strategy[END_REF]. The next section will summarize the main findings from this work, highlighting the role of several signaling molecules in mediating reconsolidation of cocaine-associated memories, using CPP and SA paradigms (see Table 1). The main goal of these studies was to reduce cocaine-associated reconsolidation and/or to enhance cocaine-associated extinction.

Target molecules uncovered in cocaine-associated reconsolidation

A premise of this work is that reconsolidation of cocaine-associated memories follows the same principles as reconsolidation of fear-associated memories, and depends on de novo protein synthesis. Indeed, several studies have disrupted cocaineassociated reconsolidation [START_REF] Fuchs | Basolateral amygdala involvement in memory reconsolidation processes that facilitate drug context-induced cocaine seeking[END_REF][START_REF] Wells | Interaction between the basolateral amygdala and dorsal hippocampus is critical for cocaine memory reconsolidation and subsequent drug context-induced cocaineseeking behavior in rats[END_REF][START_REF] Dunbar | Inhibition of protein synthesis but not β-adrenergic receptors blocks reconsolidation of a cocaine-associated cue memory[END_REF]Zhu et al., 2018) using inhibitors of protein synthesis, administered either systemically or in situ in the basolateral amygdala (BLA). In contrast, no impact on reconsolidation was observed after dorsal hippocampus (DH) or dorsal striatum (caudate putamen; CPu) inhibition [START_REF] Ramirez | Dorsal hippocampal regulation of memory reconsolidation processes that facilitate drug context-induced cocaine-seeking behavior in rats[END_REF][START_REF] Fuchs | Basolateral amygdala involvement in memory reconsolidation processes that facilitate drug context-induced cocaine seeking[END_REF]. Further dissociation of protein synthesis effects were revealed with evidence that inhibition of protein synthesis in the medial prefrontal cortex (mPFC) alters reconsolidation of memory triggered by cocaine combined with cocaine-paired cues [START_REF] Sorg | Anisomycin in the medial prefrontal cortex reduces reconsolidation of cocaine-associated memories in the rat self-administration model[END_REF], but not by a context associated with cocaine [START_REF] Ramirez | Dorsal hippocampal regulation of memory reconsolidation processes that facilitate drug context-induced cocaine-seeking behavior in rats[END_REF]. This differential outcome suggests that memories triggered by cocaine-associated context versus cocaine combined with discrete cues might be supported by different neural substrates, pathways, and/or mechanisms. Altogether, these results indicate that protein synthesis is a necessary step in cocaine-associated reconsolidation and the effect is mediated in specific brain structures. This site-specific process argues against a general effect of protein synthesis inhibition, as proposed in the statedependency theory (Gisquet-Verrier and Riccio, 2019).

Studies examining mechanisms of cocaine addiction within a reconsolidation framework have revealed several molecular targets, receptor subtypes, and intracellular pathways that contribute to this process (see table 1). Given their critical role in learning, memory, and synaptic plasticity [START_REF] Baudry | Multiple cellular cascades participate in long-term potentiation and in hippocampus-dependent learning[END_REF], it is not surprising that glutamatergic NMDA receptors (NMDARs) are heavily involved in cocaine reconsolidation. Indeed, inhibition of NMDARs, either systemically (Li et al., 2016) or directly in NAc shell [START_REF] Alaghband | Common influences of non-competitive NMDA receptor antagonists on the consolidation and reconsolidation of cocaine-cue memory[END_REF] or DH [START_REF] Wells | Contribution of an SFK-Mediated Signaling Pathway in the Dorsal Hippocampus to Cocaine-Memory Reconsolidation in Rats[END_REF], affected cocaine-associated reconsolidation. In contrast, NMDARs activation produces inconsistent effects, enhancing both cocaine-associated extinction [START_REF] Sanchez | Reconsolidation of a cocaine-associated stimulus requires amygdalar protein kinase A[END_REF] and reconsolidation [START_REF] Lee | D-cycloserine potentiates the reconsolidation of cocaine-associated memories[END_REF], resulting in opposing effects on drug-seeking behavior (i.e., decreases and increases respectively). This could represent a major limitation for therapeutic intervention as it would be difficult to limit effects to an interval that would result in the decrease of cocaine-seeking behavior.

Other molecular targets involved in learning and memory have been investigated in reconsolidation processes, such as calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA). CaMKII inhibition in the BLA weakens cocaine-associated reconsolidation and enhances extinction [START_REF] Rich | Phosphoproteomic Analysis Reveals a Novel Mechanism of CaMKIIα Regulation Inversely Induced by Cocaine Memory Extinction versus Reconsolidation[END_REF], although another study failed to produce the same effect [START_REF] Arguello | Involvement of amygdalar protein kinase A, but not calcium/calmodulin-dependent protein kinase II, in the reconsolidation of cocaine-related contextual memories in rats[END_REF]. PKA inhibition in the BLA (Shanchez et al., 2010;[START_REF] Arguello | Involvement of amygdalar protein kinase A, but not calcium/calmodulin-dependent protein kinase II, in the reconsolidation of cocaine-related contextual memories in rats[END_REF], but not in the dorsal striatum [START_REF] Arguello | Involvement of amygdalar protein kinase A, but not calcium/calmodulin-dependent protein kinase II, in the reconsolidation of cocaine-related contextual memories in rats[END_REF], disrupts cocaine-associated reconsolidation.

Altogether, these results highlight the complexity of molecular mechanisms underlying reconsolidation and extinction of cocaine-associated memories, as both involve learning processes.

Several G protein coupled receptors (GPCRs) have been targeted for modulating reconsolidation in order to reduce cocaine-seeking behaviors. For example, blocking dopaminergic D1 [START_REF] Li | NMDA and dopamine D1 receptors within NAc-shell regulate IEG proteins expression in reward circuit during cocaine memory reconsolidation[END_REF] or D3 [START_REF] Yan | Dopamine D3 receptors regulate reconsolidation of cocaine memory[END_REF] receptors reduces cocaine-seeking behavior, whereas D2 receptor blockade has no effect [START_REF] Li | NMDA and dopamine D1 receptors within NAc-shell regulate IEG proteins expression in reward circuit during cocaine memory reconsolidation[END_REF]. Inhibiting adrenergic receptors produced inconsistent results: no effect [START_REF] Dunbar | Inhibition of protein synthesis but not β-adrenergic receptors blocks reconsolidation of a cocaine-associated cue memory[END_REF] or an inhibition of cocaine-seeking behavior [START_REF] Fricks-Gleason | Post-retrieval beta-adrenergic receptor blockade: effects on extinction and reconsolidation of cocaine-cue memories[END_REF]Zhu et al., 2018). These discrepancies could be explained by different 'reconsolidation' paradigms, with single or repeated memory manipulations (i.e., one versus multiple retrieval sessions and treatments) producing different effects [START_REF] Fricks-Gleason | Post-retrieval beta-adrenergic receptor blockade: effects on extinction and reconsolidation of cocaine-cue memories[END_REF]. Moreover, reactivation by context versus cocaine also has different effects on the modulation of seeking behavior [START_REF] Dunbar | Inhibition of protein synthesis but not β-adrenergic receptors blocks reconsolidation of a cocaine-associated cue memory[END_REF]Zhu et al., 2018). This work has been applied to clinical populations of drug addicts with a study examining the efficacy of propranolol, a β-adrenergic antagonist, as a therapeutic strategy targeting reconsolidation [START_REF] Lonergan | Reactivating addiction-related memories under propranolol to reduce craving: A pilot randomized controlled trial[END_REF]. When administered immediately prior to participants reading a personalized script detailing a drug-use experience, the antagonist decreased self-reported drug-craving [START_REF] Lonergan | Reactivating addiction-related memories under propranolol to reduce craving: A pilot randomized controlled trial[END_REF], suggesting that it interfered with reconsolidation of the drug-associated memory that was reactivated during the script reading. Unfortunately, this study lacked follow-up measures on the percentage of patients who relapsed following study participation.

Recently, cannabidiol, a phytocannabinoid agonist, known to have many beneficial effects on several health conditions [START_REF] Crippa | Translational Investigation of the Therapeutic Potential of Cannabidiol (CBD): Toward a New Age[END_REF], has been shown to disrupt reconsolidation of cocaine-associated context memory in rats (de Carvalho and Takahashi, 2016). These pharmacological agents could represent promising candidates for treating relapse to cocaine use.

In addition to GPCRs, a number of intracellular signaling mechanisms have been investigated in reconsolidation processes related to cocaine administration in rodents.

Systemic or in situ (e.g., NAc or amygdala) disruption of specific pathways, including mTOR, Cdk5, eIF2α, decreases cocaine-associated reconsolidation, leading to a reduction of cocaine-seeking behavior. Some studies have examined the effect of stress on relapse-like behavior and/or cocaine-associated memories but whether this directly impacts reconsolidation is still not fully understood (see Table 1). Interestingly, cellular stress-like NOS signalling pathways disrupt reconsolidation and reduce cocaine-seeking behavior [START_REF] Itzhak | Role of the NMDA receptor and nitric oxide in memory reconsolidation of cocaine-induced conditioned place preference in mice[END_REF]. Cocaine induces transcriptional adaptations in brain structures [START_REF] Piechota | The dissection of transcriptional modules regulated by various drugs of abuse in the mouse striatum[END_REF] and some of these modifications are under the control of epigenetic factors (De Sa Nogueira et al., 2018), which themselves are involved in cocaine-associated reconsolidation. For example, intra-amygdala inhibition of DNA-methyltransferase [START_REF] Shi | Reconsolidation of a cocaine associated memory requires DNA methyltransferase activity in the basolateral amygdala[END_REF] or systemic inhibition of histone acetyltransferase (HAT) [START_REF] Monsey | The Naturally Occurring Compound Garcinia Indica Selectively Impairs the Reconsolidation of a Cocaine-Associated Memory[END_REF][START_REF] Dunbar | Garcinol Blocks the Reconsolidation of Multiple Cocaine-Paired Cues after a Single Cocaine-Reactivation Session[END_REF] disrupt reconsolidation of cocaine memories.

In conclusion, the process of reconsolidation in cocaine addiction has been demonstrated, although limitations for therapeutic interventions remain. The wide diversity of experimental paradigms, the brain areas under study, and the specificity of the pharmacological tools may explain the diverse findings on reconsolidation related to cocaine-seeking behavior. Noteably, a reactivation phase appears to be critical in this process, as reduction of seeking behavior may result from an action on either extinction or reconsolidation. Furthermore, cues, context, or cocaine reactivation involve distinct memory pathways that may be differentially altered by candidate molecules. Therapeutic approaches, even if promising, require further investigation to selectively target the reconsolidation process in cocaine addiction.

Neuroinflammation and memory

It is interesting to note that some of the pharmacological agents tested in the framework of the reconsolidation theory of cocaine addiction display antiinflammatory properties. The resulting effects on cocaine seeking behavior, therefore, could also be explained, at least partially, by an inhibition of neuroinflammation. For example, garcinol [START_REF] Monsey | The Naturally Occurring Compound Garcinia Indica Selectively Impairs the Reconsolidation of a Cocaine-Associated Memory[END_REF][START_REF] Dunbar | Garcinol Blocks the Reconsolidation of Multiple Cocaine-Paired Cues after a Single Cocaine-Reactivation Session[END_REF] is considered a HAT inhibitor, and cannabidiol (de Carvalho and Takahashi, 2016) is a "multi-target" compound which affects several channels and/or receptors, including the cannabinoid 2 receptor (CB2R) (Devinsky et al., 2016). Noticeably, both pharmacological tools also display anti-inflammatory (e.g., direct and indirect inhibiton of NFκB activation) and antioxidant (e.g., inhibition of iNOS) properties (see reviews [START_REF] Padhye | Emerging role of Garcinol, the antioxidant chalcone from Garcinia indica Choisy and its synthetic analogs[END_REF][START_REF] Kozela | Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid[END_REF]. Morover, among the molecular targets highlighted in reconsolidation of cocaine memories, some are also involved in inflammatory mechanism. For example, the -adrenergic receptor pathway, which is curently targeted in human trials, displays cross-talk with immune and inflammatory pathways (see review, [START_REF] Scanzano | Adrenergic regulation of innate immunity: a review[END_REF]. The adrenergic receptors are considered to be immunomodulators. Opposite results have been described following stimulation of β-adrenergic receptors, with either an antiinflammatory action or an enhancement of a pro-inflammatory state (see review, [START_REF] Kolmus | β2-Adrenergic receptors in immunity and inflammation: stressing NF-κB[END_REF]. In addition, other downstream signaling molecules, also studied in cocaine-associated reconsolidation, have been linked to inflammatory pathways, such as PKA [START_REF] Tao | Cannabinoid receptor-2 stimulation suppresses neuroinflammation by regulating microglial M1/M2 polarization through the cAMP/PKA pathway in an experimental GMH rat model[END_REF][START_REF] Ghosh | Cyclic AMP is a key regulator of M1 to M2a phenotypic conversion of microglia in the presence of Th2 cytokines[END_REF] and CaMKII [START_REF] Tsakiri | Interleukin-1-induced interleukin-6 synthesis is mediated by the neutral sphingomyelinase/Src kinase pathway in neurones[END_REF]. The former appears to be necessary for microglial transition from proinflammatory to anti-inflammatory states, whereas CaMKII mediates interleukine synthesis in neuronal cultures challenged for immune responses. Based on these observations, neuroinflammatory processes during cocaine reconsolidation represent an important line of further investigation.

Neuroinflammation: general process

For many years, the brain was thought to be an "immune-privileged" organ, protected by the blood brain barrier that isolates the central nervous system (CNS) from the peripheral immune system. Lately, a significant body of evidence has revealed the existence of a specific innate immune system inside the CNS which, when activated, results in neuroinflammation (see review [START_REF] Rivest | Regulation of innate immune responses in the brain[END_REF]. Microglia plays an important role in this process as they are CNS resident macrophage-derived cells and have a major role in immune surveillance [START_REF] Subramaniam | Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson's Disease[END_REF]. Besides microglia, all brain cell types (e.g., astrocytes, oligodendrocytes, and neurons) are also involved in the neuroinflammatory process.

The main pathway involved in neuroinflammatory processes is triggered by pattern recognition receptors (PRR), including pathogen-or danger-associated patterns (i.e., PAMPs and DAMPs), which address pathogen invasion or tissue damage. The most common PRR, the Toll-like receptors (TLRs), are primarily expressed on microglia, although variable combinations of TLRs are also expressed by astrocytes, neurons, and other non-neuronal cells (i.e., endothelial and oligodendrocytes) [START_REF] Hanamsagar | Toll-like receptor (TLR) and inflammasome actions in the central nervous system[END_REF]. There are approximately a dozen TLR family members in mammals, which respond to specific stimuli. Activation of all TLRs (with the exception of TLR3) induces MyD88 activation, leading to the induction of nuclear factor κ B (NFκB) and pro-inflammatory cytokine release (i.e., IL-1β, IL-6 or TNFα) [START_REF] Brown | TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk[END_REF]. In contrast, TLR3 induces a TRIF-dependent pathway leading to IRF3 activation and secretion of other cytokines, such as IFNγ, although this signaling pathway can also be triggered by TLR4 through an adaptor protein, TRAM. Both MyD88 and TRIF-dependent pathways also stimulate mitogen-associated protein kinase (MAPK) including ERK, p38, and JNK [START_REF] Brown | TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk[END_REF]. These neuroinflammatory pathways exert a critical influence on memory processes. The two following sections summarize the literature on this topic, focusing on proinflammatory cytokines expressed by both glia and neurons (i.e., IL-1, IL-6 and TNFα) (for a more detailed review, see [START_REF] Yirmiya | Immune modulation of learning, memory, neural plasticity and neurogenesis[END_REF].

Detrimental effects of neuroinflammation on memory

The majority of literature on neuroinflammation and memory supports the idea that neuroinflammation has detrimental effects on memory, which have been demonstrated, primarily, by observations in neurodegenerative diseases [START_REF] Bader | Mitochondria at the interface between neurodegeneration and neuroinflammation[END_REF]. More specifically, neuroinflammation has been associated with memory impairment in various animal paradigms that match consolidation. For example, exogenous IL-1β induces alterations in biological processes that support LTP, thereby preventing the emergence of LTP [START_REF] Katsuki | Interleukin-1 beta inhibits long-term potentiation in the CA3 region of mouse hippocampal slices[END_REF]. Moreover, exogenous IL-1β or bacterial infection that increases IL-1β, do not affect acquisition of spatial learning in the Morris water maze, but reduce performance in the retention phase [START_REF] Oitzl | Interleukin-1 beta, but not interleukin-6, impairs spatial navigation learning[END_REF][START_REF] Gibertini | Spatial learning impairment in mice infected with Legionella pneumophila or administered exogenous interleukin-1-beta[END_REF]. In the same way, lipopolysaccharide (LPS) injections [START_REF] Pugh | Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning[END_REF], or IL-1β intracerebroventricular or intrahippocampal administration [START_REF] Barrientos | Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus[END_REF] induce impairments in contextual fear conditioning. Moreover, this effect is reversed by IL-1ra (i.e., natural antagonist of IL-1 receptor) injections [START_REF] Pugh | Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning[END_REF]. Importantly, animals preexposed to the context before conditioning showed no deficit suggesting that the impairment resulted from an alteration of the context-associated consolidation processes, but not from the association between the context and the aversive stimulus [START_REF] Pugh | Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning[END_REF][START_REF] Barrientos | Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus[END_REF]. Finally, chronic neuroinflammation in transgenic mice overexpressing IL-1β has been revealed through up-regulation of inflammatory mRNAs molecules in the hippocampus [START_REF] Moore | Sustained expression of interleukin-1beta in mouse hippocampus impairs spatial memory[END_REF][START_REF] Hein | Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice[END_REF]. These mice show impairments in contextual, but not auditory, fear conditioning [START_REF] Hein | Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice[END_REF], as well as deficits in spatial learning in the water maze, which were negatively correlated with gene regulation [START_REF] Moore | Sustained expression of interleukin-1beta in mouse hippocampus impairs spatial memory[END_REF]. Chronic neuroinflammation, induced by repeated LPS infusions, has been linked to increases in TNFα, TNFR2, and IL-1β hippocampal expression [START_REF] Belarbi | TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation[END_REF].

Impairments of both acquisition and consolidation in a spatial water maze, following chronic LPS, were rescued by DT 3,6'dithiothalidomide, a blocker of TNFα activity (Belardi et al., 2012;[START_REF] Russo | 3,6'-Dithiothalidomide, a new TNF-α synthesis inhibitor, attenuates the effect of Aβ1-42 intracerebroventricular injection on hippocampal neurogenesis and memory deficit[END_REF]. Together, these results indicate that elevated level of IL-1β and TNFα, inducing neuroinflammatory processes, have a detrimental effect on contextual memory. Noticeably, high doses of proinflammatory cytokines, such as IL-1β, IL-6, or TNFα, or administration of pathogens, can induce a state of "sickness behavior" [START_REF] Lacosta | Behavioral and neurochemical consequences of lipopolysaccharide in mice: anxiogenic-like effects[END_REF]. Mice injected with IL-1β display spatial deficit only in a warm-water maze (i.e., 23°C) and not in cold-water maze (i.e., 18°C) from which they may have a stronger motivation to escape [START_REF] Gibertini | Cytokines and cognitive behavior[END_REF]) (for a review, see [START_REF] Cunningham | Malaise in the water maze: untangling the effects of LPS and IL-1beta on learning and memory[END_REF]. This state of sickness could partly account for altered memory through statedependency processes or a change in motivation.

Beneficial effects of neuroinflammatory markers on memory

Studies examining the role of pro-inflammatory markers in memory suggest that a balance of several cytokines is necessary for the establishment and maintenance of a memory trace. Tetanic bursts that induce LTP, ex vivo or in vivo, lead to hippocampal up-regulation of mRNA for a number of cytokines, such as IL-1β, IL-6 and IL-1ra, although TNFα expression is not altered [START_REF] Schneider | A neuromodulatory role of interleukin-1beta in the hippocampus[END_REF][START_REF] Balschun | Interleukin-6: a cytokine to forget[END_REF][START_REF] Del Rey | A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning[END_REF]; these effects were observed only in rats displaying persistent LTP for more than 3 hours. Importantly, prior administration of an NMDAR antagonist) prevented this upregulation. These data suggest that cytokines are involved in LTP mechanisms at a time point that matches a consolidation phase. The IL-1β cytokine plays a critical role in these processes, as no LTP could be measured in mice deficient for the IL-1 receptor (IL-1RrKO) [START_REF] Avital | Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity[END_REF]. Pharmacological intervention showed that inhibition of IL-1β, via administration of the IL-1ra antagonist 90 min after tetanic bursts, reduced population spikes to pre-LTP values [START_REF] Schneider | A neuromodulatory role of interleukin-1beta in the hippocampus[END_REF]. This effect was not observed when the antagonist was administered 30 min prior to, or 5 min after, LTP induction, indicating that IL-1β is necessary for LTP maintenance, but not induction.

An opposite effect was observed with an antibody that blocks IL-6, resulting in sustained maintenance of LTP for a longer time and increased spatial memory [START_REF] Balschun | Interleukin-6: a cytokine to forget[END_REF]. In sum, both cytokines display time-dependent effects on memory, with IL-1β being implicated in LTP maintenance and IL-6 in LTP duration.

This dual action of IL-1 and IL-6, at a time point corresponding to consolidation, reveals a complex mechanism of cytokine activation in the healthy brain. The establishment of a balance may result in a more coherent memory trace. Behavioral experiments also support this idea. Mice deficient for the IL-1 receptor [START_REF] Avital | Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity[END_REF] or overexpressing an IL-1 receptor natural antagonist (IL-1raTG) [START_REF] Goshen | A dual role for interleukin-1 in hippocampaldependent memory processes[END_REF] display impairments in spatial learning and contextual fear conditioning, but show no difference in non-spatial learning (i.e., visible platform in water maze) or auditory fear conditioning. Up-regulation of transcripts for IL-1β and IL-6, but not IL-1ra or TNFα, are observed in the hippocampus, 2 hours following spatial learning (e.g., Y-maze) [START_REF] Del Rey | A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning[END_REF] and 24 hours following fear conditioning [START_REF] Goshen | A dual role for interleukin-1 in hippocampaldependent memory processes[END_REF]. The latter effect was observed in WT, but not in IL-1rKO and IL-1raTG, mice. Taken together, these results indicate a role for IL-1β and IL-6 in contextual memory (i.e., consolidation).

The neuroinflammatory marker, TNFα, has been implicated in cognitive-associated diseases such as Alzheimer's disease [START_REF] Decourt | Targeting Tumor Necrosis Factor Alpha for Alzheimer's Disease[END_REF], but its role in memory processes is more controversial. Neuronal cell cultures exposed to TNFα displayed an increased number of AMPAR at the membrane, arguing for the involvement of TNFα in AMAPR trafficking and therefore in synaptic strength modulation [START_REF] Beattie | Control of synaptic strength by glial TNFalpha[END_REF]. Also, mice deficient for TNFR show decreased LTP and LTD in hippocampal slices [START_REF] Albensi | Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity[END_REF]. In contrast, no TNFα transcript modification was observed in the hippocampus following either LTP-induction or learning [START_REF] Del Rey | A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning[END_REF], suggesting that further research is required to unravel the specific role of TNFα in memory.

The signaling pathway for NFκB, a transcription factor initially described in the immune system but actually expressed in brain parenchyma, plays a central role in immune and inflammatory responses. NFκB can be activated by several proinflammatory cytokine signaling pathways [START_REF] Bonizzi | The two NF-kappaB activation pathways and their role in innate and adaptive immunity[END_REF] and by LTPinducing protocols [START_REF] Freudenthal | Transcription factor NF-kappaB activation after in vivo perforant path LTP in mouse hippocampus[END_REF]. Indeed, NFκB regulates LTP-induced plasticity [START_REF] Albensi | Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity[END_REF] and, among genes regulated by NFκB, some are coding proteins located at the synapses, such as PSD95, NCAM or AMPA receptor subunits [START_REF] Engelmann | Transcriptional Control of Synaptic Plasticity by Transcription Factor NF-κB[END_REF]. These findings suggest that NFκB is involved in long-term memory, a proposal that has been verified in behavioral experiments. For example, NFκB is rapidly activated in the hippocampus by contextual emotional memory [START_REF] Freudenthal | NF-kappaB transcription factor is required for inhibitory avoidance long-term memory in mice[END_REF] and in the amygdala by conditioned fear [START_REF] Yeh | A requirement of nuclear factor-kappaB activation in fear-potentiated startle[END_REF]. In addition, altering NFκB activation or disrupting NFκB activity during consolidation/reconsolidation produce memory impairments during a retention test [START_REF] Freudenthal | NF-kappaB transcription factor is required for inhibitory avoidance long-term memory in mice[END_REF][START_REF] De La Fuente | Reconsolidation or extinction: transcription factor switch in the determination of memory course after retrieval[END_REF][START_REF] De La Fuente | Calcineurin phosphatase as a negative regulator of fear memory in hippocampus: control on nuclear factor-κB signaling in consolidation and reconsolidation[END_REF]. Moreover, NFκB is inhibited following cueextinction, suggesting a complex role for this transcription factor (de la [START_REF] De La Fuente | Reconsolidation or extinction: transcription factor switch in the determination of memory course after retrieval[END_REF]. Collectively, these results indicate that extracellular signals, initially related to inflammation, could in fact play a role in physiological processes of memory consolidation and reconsolidation.

In conclusion, both detrimental and beneficial effects of cytokines on memory processes have been described, and this differential consequence is dependent on the dose of cytokines, specifically physiological (low) versus pathological (high) states (see above). In line with this idea, some studies emphasize an inverted U-shape doseeffect of IL-1 on memory [START_REF] Brennan | Low doses of interleukin-1beta improve the leverpress avoidance performance of Sprague-Dawley rats[END_REF][START_REF] Goshen | A dual role for interleukin-1 in hippocampaldependent memory processes[END_REF]. Indeed, high doses of IL-1β impair contextual fear conditioning in mice, whereas low doses enhance it [START_REF] Goshen | A dual role for interleukin-1 in hippocampaldependent memory processes[END_REF], confirming that neuroinflammation plays a role in spatial and contextual memory. Hippocampus-dependent memory is clearly modified by neuroinflammation markers, but no convincing data exist on whether other types of memories, such as cue-associated or emotional memory, are also modulated. Further exploration will bring insight into the neuroinflammatory mechanisms involved in different kind of memories. Also, as all the data on cytokines summarized here were obtained following learning (i.e., consolidation), it is critical to explore the role of these cytokines in memory retrieval. This would uncover a potential role of these cytokines in reconsolidation.

Cocaine and neuroinflammation

Drugs of abuse, and in particular alcohol, trigger neuroinflammation, although less is known about the effects of cocaine on neuroinflammation (see reviews [START_REF] Clark | Psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection[END_REF][START_REF] Lacagnina | Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse[END_REF]. Table 2 summarizes these few studies, highlighting the regulation of neuroinflammatory markers, both in vitro (cell culture) and in vivo (rodent, primate and human). In humans, chronic cocaine use is associated with increased serum levels of the pro-inflammatory cytokine, IL-6, and decreased serum levels of the anti-inflammatory cytokine, IL-10 ( Moreira et al., 2015), pointing to a global pro-inflammatory effect. This idea is supported by evidence of enhanced microglia activation in post-mortem brains of cocaine users [START_REF] Little | Decreased brain dopamine cell numbers in human cocaine users[END_REF]. In contrast, no difference in microglia activation in grey matter was observed in living cocaine users, using a positron emission tomography (PET) imaging technique [START_REF] Narendran | Cocaine abuse in humans is not associated with increased microglial activation: an 18-kDa translocator protein positron emission tomography imaging study with [11C]PBR28[END_REF]. Patients in the PET study were abstinent for a minimum of 14 days, whereas individuals in the post-mortem study had used cocaine at least once in the 2 weeks prior to death. Neuroinflammation induced by cocaine, therefore, may not persist beyond a 2-week interval. The discrepancy could also reflect differences in the brain region investigated (grey versus white matter). Indeed, microglia activation in living nonhuman primates increased, specifically in white matter, following cocaine use [START_REF] Smith | Regional elevations in microglial activation and cerebral glucose utilization in frontal white matter tracts of rhesus monkeys following prolonged cocaine self-administration[END_REF].

Further work has examined potential mechanisms involved in pro-inflammatory consequences of cocaine use. The cocaine-induced "xenobiotic hypothesis" proposes that cocaine is recognized by the immune system as a foreign xenobiotic component (see review [START_REF] Hutchinson | Why is neuroimmunopharmacology crucial for the future of addiction research?[END_REF]. Indeed, cocaine binds directly to the MD2 domain of TLR4 in the VTA [START_REF] Northcutt | DAT isn't all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling[END_REF], a PRR known to be triggered by xenobiotic components [START_REF] Hutchinson | Why is neuroimmunopharmacology crucial for the future of addiction research?[END_REF]. The interaction with TLR4 further increases DA release in the NAc [START_REF] Northcutt | DAT isn't all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling[END_REF], which suggests a synergetic effect with the direct action of cocaine on monoamine-reuptake transporters. Furthermore, several downstream elements of a TLR4 pathway are up-regulated by cocaine, both in vitro and in vivo (see Table 2), including NFκB, IL-1β, IL-6, IL-12, TNFα, MAPK, IRAK1, MyD88, and TRAF6. In addition, downregulation of IL-10 has been reported following cocaine intake [START_REF] Ang | Induction of nuclear factor-kappaB in nucleus accumbens by chronic cocaine administration[END_REF][START_REF] Russo | Nuclear factor kappa B signaling regulates neuronal morphology and cocaine reward[END_REF][START_REF] Lin | Memantine abolishes the formation of cocaine-induced conditioned place preference possibly via its IL-6-modulating effect in medial prefrontal cortex[END_REF]Moreira et al., 2015;[START_REF] Liao | Cocaine-mediated induction of microglial activation involves the ER stress-TLR2 axis[END_REF]Brown et al., 2017;Zhu et al., 2018b;[START_REF] Periyasamy | Cocaine-Mediated Downregulation of miR-124 Activates Microglia by Targeting KLF4 and TLR4 Signaling[END_REF], again supporting a global proinflammatory process. Cocaine also indirectly enhances proinflammatory markers through other TLRs, including TLR2 and TLR3 [START_REF] Liao | Cocaine-mediated induction of microglial activation involves the ER stress-TLR2 axis[END_REF]Zhu et al., 2018b), that could participate in the downstream regulations observed. In sum, targeted approaches have revealed the importance of TLRs pathways in inflammatory processes following cocaine exposure.

Interestingly, genome-wide approaches have also pointed to regulation of a wide variety of inflammatory molecules following cocaine intake. For example, analysis of genomic data [START_REF] Clark | Psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection[END_REF] obtained from whole RNA sequencing studies [START_REF] Ahmed | Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction[END_REF][START_REF] Renthal | Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli[END_REF][START_REF] Piechota | The dissection of transcriptional modules regulated by various drugs of abuse in the mouse striatum[END_REF] highlight gene expression increases in inflammatory modulators in several brain reward structures (e.g., dorsal striatum, NAc, PFC, amygdala, septum, lateral hypothalamus, and VTA), following acute or chronic cocaine intake in rats. A global increase in neuroinflammatory marker expression was confirmed in an RNAseq study of both NAc and VTA samples from cocaine self-administering nonhuman primates [START_REF] Vallender | Transcriptomic profiling of the ventral tegmental area and nucleus accumbens in rhesus macaques following long-term cocaine selfadministration[END_REF]. Pro-inflammatory cytokines, cytokine receptors, chemokines, TLRs, MMPs, ADAMs, PDGFs, and MCSF are among the genes up-regulated by cocaine. These data highlight novel candidates involved in cocaineinduced adaptations, in addition to those identified in targeted approaches.

Overall, cocaine intake is consistently associated with increases in a number of neuroinflammatory markers. Several drugs of abuse cause activation of microglia and astrocytes through signaling of neuroinflammatory markers, which influence neuronal function [START_REF] Lacagnina | Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse[END_REF]. Blocking this brain reaction to cocaine by anti-inflammatory strategies, both in rodents and humans, has shown efficacy in alcohol abuse treatment by acting on drug intake, craving, or relapse (see reviews [START_REF] Ray | Opportunities for the development of neuroimmune therapies in addiction[END_REF]Konho et al., 2019). Few studies have examined the effect of antiinflammatory agents in cocaine addiction, although these have produced intriguing results. For example, administration of (+)naltrexone, a specific TLR4 antagonist, prevents the development of cocaine place preference in rats [START_REF] Northcutt | DAT isn't all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling[END_REF]. N-acetylcysteine is an antioxidant and anti-inflammatory agent which has been examined for treating several psychiatric and neurological disorders associated with dysfunction in oxidative stress, neuroinflammation, as well as, glutamate and dopamine dysregulation (see review [START_REF] Deepmala | Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review[END_REF]. Interestingly, Nacetylcysteine displays promising anti-relapse effects both in pre-clinical and clinical studies (for a review, see Nocito [START_REF] Echevarria | N-acetylcysteine for treating cocaine addiction -A systematic review[END_REF]. Indeed, in clinical studies, N-acetylcysteine decreased desire and interest toward cocaine when given after a cue-reactivity procedure (i.e., slides depicting cocaine and cocaine-use) [START_REF] Larowe | Is cocaine desire reduced by N-acetylcysteine?[END_REF]. The drug also increases time to relapse and reduces craving in abstinent addicts, whereas it had no effect on craving or drug intake in cocaine consumers at the time of the experiment [START_REF] Larowe | A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence[END_REF]. These results are supported by preclinical studies in rodents. In a long-access paradigm inducing escalation, N-acetylcysteine prevents increased cocaine intake and blocks cocaine-induced locomotor sensitization as well as cocaine-induced reinstatement [START_REF] Madayag | Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine[END_REF]. In contrast, it had no effect on cocaine intake per se in humans [START_REF] Madayag | Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine[END_REF]. Altogether, N-acetylcysteine represents a good candidate for intervention in cocaine abstinent patients. Further investigation exploring other inflammatory markers induced by cocaine could provide informative data for developing novel strategies to reduce cocaine-relapse.

Conclusions

The idea that addiction may reflect maladaptive memory has emerged, with an emphasis on developing therapeutic strategies to counter recurrent relapse in cocaine addiction. Numerous animal studies confirm that disruption of cocaine-associated memories (i.e., reconsolidation) decreases cocaine-seeking behavior. Based on this evidence, a combination of behavioral and pharmacological treatments should be further investigated in human clinical trials. Uncovering the underlying mechanisms of cocaine-associated memories will help to target pathways and time points of effective therapeutic strategies. Indeed, some of the results summarized above suggest that mechanisms other than reconsolidation (e.g., disruption in extinction or impairment in retrieval) may contribute to this process. Therefore, the retrieval protocol and the time window within which pharmacological or behavioral interventions occur are essential elements in the ensuing alterations of cocaineseeking behavior.

Among potential lines of investigation, neuroinflammation is an intriguing possibility. Indeed, many neuroinflammatory markers, such as pro-inflammatory cytokines or their upstream regulator NFκB, are up-regulated by cocaine intake.

Development of a pro-inflammatory state has been confirmed by targeted and wholegenome approaches. Such cytokines are crucial players in memory processes, with the specific impact depending on the intensity and duration of the inflammatory process. Further work is required in this area, but it is now clear that interactions between memory processes and neuroinflammation following cocaine use could represent new targets for therapeutic interventions to reduce relapse. Among molecules involved in both neuroinflammation and memory, factors like NFκB represent an appealing target. We have previously shown that rats that selfadminister cocaine display differential epigenetic regulation of genes organized around this transcription factor [START_REF] Fonteneau | Inhibition of DNA methyltransferases regulates cocaine self-administration by rats: a genome-wide DNA methylation study[END_REF]. Moreover, genome-wide association studies in cocaine users, focusing on genes related to learning, memory, and synaptic plasticity, have highlighted two single nucleotide polymorphisms on nfkb1, encoding for NFκBp105/p50 [START_REF] Levran | Synaptic Plasticity and Signal Transduction Gene Polymorphisms and Vulnerability to Drug Addictions in Populations of European or African Ancestry[END_REF]. In addition, investigations of reconsolidation processes have revealed that inhibition of NFκB can disrupt fearassociated reconsolidation (de la [START_REF] De La Fuente | Reconsolidation or extinction: transcription factor switch in the determination of memory course after retrieval[END_REF] or morphine-CPP associated reconsolidation [START_REF] Yang | Inhibition of nuclear factor-κB impairs reconsolidation of morphine reward memory in rats[END_REF]. Hence, acting on the NFκB pathway may be an appropriate approach to disrupt cocaine-associated reconsolidation and, therefore, decrease relapse.

Among the strategies proposed to directly impact reconsolidation of cocaine memories, the β-adrenergic blocker, propranolol, is under investigation at the clinical level and displays promising effects. Another target for cocaine-associated memory could be N-acetylcysteine. Indeed, the anti-reinstatement effect of this compound could also be explained by the restoration of neuroplasticity at cortico-striatal synapses induced through its action on the cysteine-glutamate exchanger [START_REF] Madayag | Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine[END_REF][START_REF] Moussawi | N-Acetylcysteine reverses cocaine-induced metaplasticity[END_REF]. This inability to use neuroplasticity could explain, at least partially, the difficulties of addict individuals to learn new behaviors to reduce cocaine intake. Moreover, as N-acetylcysteine decreases craving in humans when given after cue-retrieval [START_REF] Larowe | Is cocaine desire reduced by N-acetylcysteine?[END_REF], it could provide beneficial effects on cocaine-associated reconsolidation. Remarkably, both propranolol and Nacetylcysteine also have anti-inflammatory properties that could account for their ability to reduce relapse. As with many mental health disorders, pharmacological treatments for cocaine abuse are often more effective when combined with behavior modification programs. Of these, cognitive behavioral therapy (CBT), is one of the most effective, particularly in terms of increasing treatment retention and reducing relapse [START_REF] Penberthy | Review of treatment for cocaine dependence[END_REF]. Although it has yet to be tested, principles of reconsolidation could be incorporated into CBT treatment by raising patient awareness of cue-drug associations and how these are modified with repeated memory reactivation. Altogether, it appears that developing a strategy combining anti-inflammatory agents, cocaine-associated memory manipulations, and CBT could hold promising treatment for altering cocaine-seeking behavior.

  Theory of reconsolidation for cocaine addiction 3.2.Target molecules uncovered in cocaine-associated reconsolidation

  De Sa Nogueira, D., Merienne, K., Befort, K., 2018. Neuroepigenetics and addictive

	behaviors: Rat Rat	Where (1.0mg/kg SA ) Extinction do CPP (10mg/kg) None	we Cue reactivation, Context B, 3x Context Cue extinction, Context B, reactivation, All compartments, 60/120x 15min	stand? KN-62 KN-62 Nadolol	Neurosci BLA BLA DH	Biobehav Cue-induced reinstatement Daily tests Cocaine priming test	--+ o	Rev. Rich et al., 2016 Otis et al., 2014
	Focus	Species Rat Rat Mouse Rat Rat	Paradigm CPP (10mg/kg) SA (0.5mg/kg ) CPP (20mg/kg) SA (1mg/kg) CPP (10mg/kg)	Pre-manipulati on None Extinction None Extinction None	Manipulation Context reactivation, Drug-paired compartment, 3min, 1x or 5x Cue reactivation, Context B, 3x Context reactivation, Drug-paired compartment, 3min Cue reactivation, context B, 3x Context reactivation, Cue extinction, Context B, 120x Drug-paired compartment, 10min	Pharmacological/Behaviora l intervention Context-extinction, All Rp-cAMPS PG01037 compartments, 15min, 5x Reconditionning, Drug-paired compartment, 30min, 1x 8-CPT RO5166017	Site interventio of n BLA Systemic None BLA Systemic	Test Cocaine priming test 2 Cue-induced reinstatement Cocaine-induced Test 2 reinstatment 2 Test 2 Cue-induced reinstatement Test 2 Cocaine priming test 2	Effect Reference -Shanchez et al., 2010 Yan et al., -2013 o -Sartor and Aston-Jones, 2014 + -Wan et al., 2014 o Liu et al., 2016
					Context							o
				None	Cue reactivation, Context B, 3x extinction, All compartments,	6-Bnz					Test 2
					Xmin, 6x
	Conditioning	Mouse Rat Rat Rat Rat Rat Rat	CPP (15mg/kg) SA (0.25mg/k g) SA (0.25mg/k g) CPP (10mg/kg) SA (0.5mg/kg ) SA (0.15mg/in j) SA (0.5mg/kg ) CPP (10mg/kg)	None Forced abstinence Forced abstinence Forced abstinence Extinction Exinction, Context B Extinction Extinction	Context reactivation, Drug-paired compartment, 4min, 4x Cue reactivation, Context A, 30x Context Cue reactivation, Context A, 30x reactivation, Drug-paired compartment, 10min Cue reactivation, Contexte B, 3x Cue extinction, Context A, 120x Context reactivation, Context A, 15min Cocaine (10mg/kg, i.p.) + Cue extinction, Context B, 120x Context reactivation, compartment, Drug-paired	Counterconditioning, Lithium chloride (LiCl)-induced malaise (150 mg/kg; i.p.), Drug-paired compartment, 4x Zif268 ASO D-cycloserine Cannabidiol Cycloheximide PP2 PEAQX tetrasodium hydrate D-cycloserine	Systemic BLA BLA Systemic Systemic Systemic DH IL, PrL, LA, DH	Cocaine priming test 2 Cue-induced reinstatement Cue-induced reinstatement Test 2 Context-Cue-induced reinstatement induced reinstatement Context-induced reinstatement Cue-induced reinstatement Test 2	--+ ----+ -o +	Goltseker et al., 2017 Lee et al., de 2006 Lee et al., 2009 Carvalho and Takahashi, 2016 Dunbar and Wells et al., 2016 Taylor, 2016 Torregross a et al., 2010
		Rat Rat Rat Rat	SA (0.5mg/kg ) SA (0.2mg/inj ) SA (0.15mg/in j) SA (0.75mg/k g)	None Forced abstinence Extinction, Context B Extinction context B	Cue (contingents) Cue reactivation, Context B, 3x 10min Cue reactivation, Contexte A, 5min Context reactivation, Context A, 15min Context reactivation, Context A, (contingents) + contexte reactivaton, Context A, 15min 15min Context	Anisomycin Calpain inhibitor mixture Anisomycine Rp-cAMPS KN-93		mPFC NAc NAc core DH, dmPFC or dlCPu BLA pCPu BLA BLA	cue-induced reinstatement Context-induced reinstatement Context-induced Cue-induced reinstatement reinstatement	o -o o -o -	Sorg et al., 2015 Liang et al., 2017 Ramirez et Arguello et al., 2014 al., 2009
		Rat Rat	SA (0.10 mg/inj) CPP (10mg/kg)	Exinction, Context B None	Context reactivation, Context 15/60min 2x Cocaine reactivation, Drug-paired compartment, (10mg/kg, i.p.) A, reactivation, HC, 10min	Anisomycine Anisomycine Sal003			BLA pCPU CeA		Context-induced reinstatement Test 2	o -o o	Fuchs et al., 2009 Jian et al., 2014
	Protein synthesis Learning mechanism signaling Intracellular	Rat Mouse Rat Rat Rat Rat Mouse Rat	SA (0.15mg/k g) CPP (15mg/kg) CPP (12mg/kg) CPP (10mg/kg) SA (0.75mg/k g) CPP (10mg/kg) CPP (10mg/kg) CPP (10mg/kg) CPP (10mg/kg)	Exinction, Context B None Exinction None None None None None	5min Context reactivation, Context 15min Cocaine (10mg/kg, i.p.) + A, context reactivation, all compartments, Context reactivation, Drug-paired compartment, 10min 15min, 2x Cocaine (1.5mg/kg, i.p.) reactivation, HC Context reactivation, all Cocaine (10mg/kg, i.p.) + cue (contingents) Context reactivation, Drug-paired compartment, 10min reactivation, compartments, 5min Cocaine (1.5mg/kg, i.p.) reactivation, HC Context reactivation, all compartments, Context A, Context 15min, 2x Context reactivation, all compartments, 15min reactivation, Drug-paired compartment, 10min Context reactivation, Drug-paired compartment, 10min	Anisomycine muscimol/baclofen (DH) (BLA) MK-801 β-butyrolactone Cycloheximide Rapamycin Zif268 ASO SB216763 NSC23766	+	BLA + DH Systemic BLA CeA Systemic Systemic BLA Systemic NAc core NAc core NAc shell	Context-induced reinstatement Cocaine-induced reinstatement Test 2 Test 2 Test 2 Cocaine priming test 2 Cocaine priming test 2 Test 2 Test 2 Test 2	---o -o -o --o	Wells al., 2011 Brown et et Li et al., 2010 al., 2008 Zhu et al., 2018 Lin et al., 2014 Shi et al., 2014 Théberge et al., 2010 Ding et al., 2013

Acknowledgements: This work was supported by Université de Strasbourg, Investissements d'Avenir Idex, Centre National de la Recherche Scientifique (CNRS), Projet International de Coopération Scientifique (PICS), and Natural Sciences and Engineering Research Council of Canada (NSERC).