Y # Pelloux
email: christelle.baunez@univ-amu.fr

Social modulation of drug use and drug addiction

This review aims to demonstrate how social science and behavioral neurosciences have highlighted the influence of social interactions on drug use in animal models. In neurosciences, the effect of global social context that are distal from drug use has been widely studied. For human and other social animals such as monkeys and rodents, positive social interactions are rewarding, can overcome drug reward and, in all, protect from drug use. In contrast, as other types of stress, negative social experiences facilitate the development and maintenance of drug abuse. However, interest recently emerged in the effect of so-called "proximal" social factors, that is, social interactions during drug-taking. These recent studies have characterized the role of the drug considered, the sharing of drug experience and the familiarity of the peer which interaction are made with. We also examine the few studies regarding the sensorial mediator of social behaviors and critically review the neural mediation of social factors on drug use. However, despite considerable characterization of the factors modulating distal influences, the mechanisms for proximal influences on drug use remain largely unknown.

Introduction

Drug addiction is a psychiatric condition that is not the mere use of drugs but instead is defined by the loss of control over its consumption and by the compulsive and obsessive use of the substance. Not everybody shifts from recreational consumption to abusive and addictive use. Thus, finding the factors promoting or preventing drug use and drug addiction such as social factors is therefore of primary interest. While clinical studies have demonstrated the effect of the social factors on drug use, it is only recently that neuroscience have been diligently looking at the effect of social factors on drug use and addiction in animal models (for review see [START_REF] Heilig | Time to connect: bringing social context into addiction neuroscience[END_REF]. This review aims to demonstrate how behavioral neurosciences have highlighted the influence of social interactions on drug use in animal models. The influence of social factors can be distal from drug use, which means it is occurring at a different time from when the drug is experienced. These factors comprise social housing (grouped or isolated), previous social experiences (prosocial or agonistic) or hierarchical status. Recently, interest have grown for the effect of social factors that are proximal from drug use, those that are present at the same time as drug is experienced. The distinction is important because prosocial and agonistic social interactions do not have the same effect whether they are experienced in the drug context or not (for review see [START_REF] Neisewander | Emotional valence and context of social influences on drug abuse-related behavior in animal models of social stress and prosocial interaction[END_REF]. Epidemiological data [START_REF] Walden | Identifying shared environmental contributions to early substance use: the respective roles of peers and parents[END_REF][START_REF] Bahr | Parental and peer influences on the risk of adolescent drug use[END_REF][START_REF] Simons-Morton | Over time relationships between early adolescent and peer substance use[END_REF] suggest that proximal social factors may be as important, and possibly more important, than distal social factors (for review see [START_REF] Strickland | The effects of social contact on drug use: behavioral mechanisms controlling drug intake[END_REF].

We will present how distal and proximal social factors prompt or prevent subjects to initiate, maintain or resume drug use. We will also review the sensory modalities and neural substrate that mediate such processes. Human and other nonhuman animals such as rodents live socially. It has been known for several decades that, rats and mice are social animals (for reviews see Barnett, 1967;[START_REF] Lore | Rat societies[END_REF][START_REF] Blanchard | The colony model: Experience counts: A reply to Lore, Nikoletseas, and Flannelly[END_REF], making them a good model for studying neuroscience on these issues and this review will focus on animal studies.

Distal social factors

As for the species, social life has many advantages in terms of reproduction, defense, foraging and even survival. For the individual of a social species, the everyday social context has prolonged effects on affective and cognitive processes. These effects can extend distally over other contexts such as the drug context and thus participate in the decision to take the drug.

The lack of social interactions or negative social interactions in the home-cage are aversive and predispose to drug use

As the individual switches from recreational to addictive use, "important social activities are given up or reduced due to substance use" (Association, 2013). Drug addictive individuals often suffers from social isolation and exclusion which can participate to the maintenance of drug use. Isolation and rejection are among the social factors associated with higher rates of male drug use (Aloise- [START_REF] Kaeppner | Sociometric status as a predictor of onset and progression in adolescent cigarette smoking[END_REF][START_REF] Rusby | Relationships Between Peer Harassment and Adolescent Problem Behaviors[END_REF]. On the other hand, cessation of drug use has better chance of success when the individuals have the social support from family and friends. A healthy family environment, which can be considered an enriched environment for animals, is associated with lower rates of drug use in humans [START_REF] Barnes | Parental Support and Control as Predictors of Adolescent Drinking, Delinquency, and Related Problem Behaviors[END_REF].

Social isolation and loneliness are aversive and, when experienced chronically, have detrimental effects on mental and physical health [START_REF] House | Social relationships and health[END_REF]. In rodents, the solitary housing over extended period (2 to 13 weeks) is a potent stressor accompanied by the deterioration of health [START_REF] Hatch | Isolation syndrome in the rat[END_REF][START_REF] Spani | Higher heart rate of laboratory mice housed individually vs in pairs[END_REF][START_REF] Carnevali | Social defeat and isolation induce clear signs of a depression-like state, but modest cardiac alterations in wild-type rats[END_REF] and behavioral alteration resembling anxiety or depressive disorders [START_REF] Weiss | Effect of social isolation on stress-related behavioural and neuroendocrine state in the rat[END_REF][START_REF] Stairs | Environmental-induced differences in corticosterone and glucocorticoid receptor blockade of amphetamine selfadministration in rats[END_REF], referred as the "isolation syndrome" (for review see [START_REF] Valzelli | The "isolation syndrome" in mice[END_REF].

In addition to the affective and cognitive disturbance of social isolation, it also alters social behavior and this effect depend on sex and stage of development. For instance, group-housed male and female adult rats do not develop CPP for social interaction. Group-housed male and female adolescent rats only develop a preference for social interaction with a grouped-housed, but not with an isolated congener. However, isolation period increases the rewarding effect of social interaction, at various development stages, with adolescent males showing the strongest preference [START_REF] Douglas | Rewarding properties of social interactions in adolescent and adult male and female rats: impact of social versus isolate housing of subjects and partners[END_REF]. Applied during adolescence, social isolation impedes social play and the social competence acquired from it. For instance, social isolation during adolescence, disrupt rats' ability, once adults, to assume a submissive posture during an encounter with a dominant, territorial rat (Van den [START_REF] Van Den Berg | Play is indispensable for an adequate development of coping with social challenges in the rat[END_REF][START_REF] Frijtag | Individual housing during the play period results in changed responses to and consequences of a psychosocial stress situation in rats[END_REF]. In addition, in the absence of an aggressor, the isolates show less putative de-arousal behaviors, such as grooming and play [START_REF] Frijtag | Individual housing during the play period results in changed responses to and consequences of a psychosocial stress situation in rats[END_REF].

In the seminal "Rat Park' study of [START_REF] Alexander | The effect of housing and gender on morphine self-administration in rats[END_REF], the authors showed that isolated rats have an exacerbated consumption of a solution of morphine on contrary to socially housed animals, which show little appetence for it. The results have since been replicated and found to be abolished by short-or long-term reversal of housing conditions [START_REF] Raz | Social isolation increases morphine intake: behavioral and psychopharmacological aspects[END_REF]. Most studies have also reported decreased social drinking of alcohol compared to isolated drinking (for review see [START_REF] Ryabinin | Assessing Social Alcohol Drinking in Rodent Models: Are We There Yet?[END_REF]. The literature has also provided extended evidence for the predisposing effect of social isolation on drug use in adolescent and adult rats, and monkey (for reviews see [START_REF] Miczek | Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake[END_REF][START_REF] Stairs | Neurobehavioral Effects of Environmental Enrichment and Drug Abuse Vulnerability[END_REF][START_REF] Trezza | Evaluating the rewarding nature of social interactions in laboratory animals[END_REF][START_REF] Nader | NONHUMAN PRIMATE MODELS OF SOCIAL BEHAVIOR AND COCAINE ABUSE[END_REF][START_REF] Neisewander | Emotional valence and context of social influences on drug abuse-related behavior in animal models of social stress and prosocial interaction[END_REF][START_REF] Bardo | Individual differences and social influences on the neurobehavioral pharmacology of abused drugs[END_REF]. Here, we quickly review some key studies characterizing the effect of social isolation on responses to drug of abuse. Isolated rats show a decreased acute locomotor response to the stimulant drugs amphetamine and nicotine [START_REF] Bowling | The effect of environmental enrichment on amphetamine-stimulated locomotor activity, dopamine synthesis and dopamine release[END_REF][START_REF] Green | Environmental enrichment decreases nicotine-induced hyperactivity in rats[END_REF]. Using the conditioned place preference procedure (CPP) where animals associate non-contingent drug injections with a specific context, isolated rats show a reduced preference for the compartment associated with amphetamine, nicotine or opiates relative to rats housed in enriched conditions (EC) [START_REF] Bowling | Locomotor and rewarding effects of amphetamine in enriched, social, and isolate reared rats[END_REF][START_REF] Smith | Social and environmental influences on opioid sensitivity in rats: importance of an opioid's relative efficacy at the mu-receptor[END_REF][START_REF] Ewin | The effects of environmental enrichment on nicotine condition place preference in male rats[END_REF], but increased cocaine induced CPP at high dose (potentially aversive) when compared to rats housed in standard conditions [START_REF] Zakharova | Social and physical environment alter cocaine conditioned place preference and dopaminergic markers in adolescent male rats[END_REF]. These results suggest a reduced sensitivity of isolated animals to the positive and aversive subjective properties of drugs. Over repeated experience with drugs, isolated animals show a greater sensitization to the stimulant effect of amphetamine or cocaine, relative to EC [START_REF] Bardo | Environmental enrichment attenuates locomotor sensitization, but not in vitro dopamine release, induced by amphetamine[END_REF][START_REF] Smith | Post-weaning housing conditions influence the behavioural effects of cocaine and d-amphetamine[END_REF], and compared with animals housed in standard condition. They also readily acquire an operant response to receive infusions of cocaine when grouped rats fail to reliably self-administer this drug at this dose [START_REF] Schenk | Cocaine self-administration in rats influenced by environmental conditions: implications for the etiology of drug abuse[END_REF]. They maintain a greater self-administration of low unit doses of amphetamine [START_REF] Bardo | Environmental enrichment decreases intravenous self-administration of amphetamine in female and male rats[END_REF][START_REF] Green | Environmental enrichment decreases intravenous amphetamine self-administration in rats: dose-response functions for fixed-and progressive-ratio schedules[END_REF] or heroin, although for the latter, difference between isolated and grouped animals dissipate after one week [START_REF] Bozarth | Influence of housing conditions on the acquisition of intravenous heroin and cocaine self-administration in rats[END_REF]. The transitory effect of social housing on heroin self-administration parallels studies on another sedative drug of abuse, showing greater consumption of alcohol of isolated animals at early but not later stages [START_REF] Wolffgramm | Social behavior, dominance, and social deprivation of rats determine drug choice[END_REF]. Finally, isolated animals seem more prone to relapse showing a greater heroin induced CPP after extinction [START_REF] Turner | Effects of Single Compared with Pair Housing on Hypothalamic-Pituitary-Adrenal Axis Activity and Low-Dose Heroin Place Conditioning in Adult Male Sprague-Dawley Rats[END_REF].

Most experiments have been conducted on adult males but increasing studies are comparing the influence of sex or development stages. Social isolation initially reduces self-administration of nicotine in males, but enhances nicotine intake during later sessions especially in females [START_REF] Peartree | Social context has differential effects on acquisition of nicotine self-administration in male and female rats[END_REF]. Adolescent Sprague-Dawley rats female rats consumed more sweetener-supplemented alcohol in isolation than when group-housed while in the same studies adolescent and adult male consume more alcohol in triads versus when isolate-housed [START_REF] Varlinskaya | Ethanol Intake Under Social Circumstances or Alone in Sprague-Dawley Rats: Impact of Age, Sex, Social Activity, and Social Anxiety-Like Behavior[END_REF]. This suggest that female might be more vulnerable to the predisposition effect of isolation on drug use. This agrees early studies demonstrating isolation seems more stressful for females than for males (for review see [START_REF] Palanza | Animal models of anxiety and depression: how are females different?[END_REF]. [START_REF] Douglas | Rewarding properties of social interactions in adolescent and adult male and female rats: impact of social versus isolate housing of subjects and partners[END_REF] found that isolation enhances social conditioned place preference more in males than females. This could suggest either that males are more affected by isolation stress on contrary to what suggested previously. Otherwise, this could suggest that the incentive for social interaction and stress induced by social isolation are dissociable processes that are differentially affected by the sex. The fact that social isolation during adolescence increase the vulnerability to take drugs is not surprising considering the importance of social interaction on the affective and cognitive development (for reviews see [START_REF] Butler | Adolescent Social Isolation as a Model of Heightened Vulnerability to Comorbid Alcoholism and Anxiety Disorders[END_REF][START_REF] Burke | Impact of adolescent social experiences on behavior and neural circuits implicated in mental illnesses[END_REF].

All these results suggest that social interactions in rodents protect from developing and maintaining drug use. As a word of caution, previously isolated rats transferred to social housing conditions increases ethanol consumption [START_REF] Weisinger | Voluntary ethanol intake of individually-or pair-housed rats: effect of ACTH or dexamethasone treatment[END_REF], suggesting a shift in housing conditions could be even more stressful than social isolation and therefore promote drug use. Moreover, it is still unclear whether the stressful effect of social isolation results from the lack of social interaction per se or from general environmental impoverishment. Analysis of behavioral and neuroanatomical changes caused by an enriched or an impoverished environment suggests that the effects of social and non-social environment are due to different mechanisms [START_REF] Rosenzweig | Social grouping cannot account for cerebral effects of enriched environments[END_REF][START_REF] Renner | Social interactions among rats housed in grouped and enriched conditions[END_REF]. Also, enrichment only partially reverses the social isolation syndrome [START_REF] Hellemans | Adolescent enrichment partially reverses the social isolation syndrome[END_REF][START_REF] Grippo | The effects of environmental enrichment on depressive and anxiety-relevant behaviors in socially isolated prairie voles[END_REF]. The question remains important as compelling evidences have demonstrated the clear protective effect of enrichment on the development and maintenance of drug use [START_REF] Solinas | Reversal of cocaine addiction by environmental enrichment[END_REF] and the protective effect of social interactions may originate from global stimulation of living in groups rather than from social bonding or reward.

Avoiding the adverse consequence of social isolation and seeking the reward of social interaction may ground the cohesion of the group [START_REF] Panksepp | Social reward among juvenile mice[END_REF]. However, in social living groups, members are likely to compete for access to limited resources, territories and mating opportunities. Chronic social stress from continuous conflicts can make relationships unstable and stressful [START_REF] Nyuyki | Chronic subordinate colony housing (CSC) as a model of chronic psychosocial stress in male rats[END_REF] and can have deleterious effect on health (for review see Lazarus, 1986). Rodents have a greater response to social defeat than other physical stressors (for reviews see [START_REF] Koolhaas | Social stress in rats and mice[END_REF][START_REF] Blanchard | Chronic social stress: changes in behavioral and physiological indices of emotion[END_REF][START_REF] Sgoifo | The socially stressed heart. Insights from studies in rodents[END_REF], and do not appear to develop adaptation against it [START_REF] Tornatzky | Long-term impairment of autonomic circadian rhythms after brief intermittent social stress[END_REF][START_REF] Sgoifo | Intermittent exposure to social defeat and open-field test in rats: acute and longterm effects on ECG, body temperature and physical activity[END_REF][START_REF] Covington | Intense cocaine self-administration after episodic social defeat stress, but not after aggressive behavior: dissociation from corticosterone activation[END_REF]. Hence, social defeat produces longerterm impacts on physical and mental health (for reviews see [START_REF] Martinez | Social defeat and subordination as models of social stress in laboratory rodents: a review[END_REF][START_REF] Sgoifo | Social stress, autonomic neural activation, and cardiac activity in rats[END_REF].

In line with the extensive literature on the precipitating role of stress on drug use and drug addiction, episodic social defeat of adult rats has been shown to promote the acquisition [START_REF] Haney | Social stress increases the acquisition of cocaine self-administration in male and female rats[END_REF][START_REF] Kabbaj | Social defeat alters the acquisition of cocaine self-administration in rats: role of individual differences in cocaine-taking behavior[END_REF] and the maintenance of cocaine self-administration [START_REF] Covington | Intense cocaine self-administration after episodic social defeat stress, but not after aggressive behavior: dissociation from corticosterone activation[END_REF][START_REF] Covington | NMDA receptors in the rat VTA: a critical site for social stress to intensify cocaine taking[END_REF], increasing the motivation for the drug [START_REF] Covington | NMDA receptors in the rat VTA: a critical site for social stress to intensify cocaine taking[END_REF][START_REF] Quadros | Two modes of intense cocaine bingeing: increased persistence after social defeat stress and increased rate of intake due to extended access conditions in rats[END_REF] and prompting binge use [START_REF] Miczek | Escalated or suppressed cocaine reward, tegmental BDNF, and accumbal dopamine caused by episodic versus continuous social stress in rats[END_REF]. In addition, social defeat or its reminder increase the reinstatement of extinguished alcohol or morphine seeking behavior [START_REF] Funk | Effects of unconditioned and conditioned social defeat on alcohol self-administration and reinstatement of alcohol seeking in rats[END_REF][START_REF] Couto | Social stress is as effective as physical stress in reinstating morphine-induced place preference in mice[END_REF].

Social rank in the home-cage has a complex effect on stress and the predisposition to drug use

While continuous conflicts make relationships unstable and stressful, social hierarchy stabilizes and appeases the group [START_REF] Durkheim | The Division of Labor in Society (WD Halls, Trans.)[END_REF][START_REF] Marx | Early writings: Translated and edited by TB Bottomore[END_REF]. It is therefore not surprising that group-housed rats form social hierarchy. It is possible to measure the dominance ratio of two animals by several means that we will quickly review here.

-Social interactions between male adult rats during dyadic encounter in the home cage of one of the individuals such as in the resident/intruder test evoke strong aggressive behavior from the resident to affirm dominance over its territory and strong submissive behaviors from the intruder [START_REF] Martinez | Social defeat and subordination as models of social stress in laboratory rodents: a review[END_REF]. However social status here is mainly driven by the experimenter and does not reflect the complex social and non-social behavior occurring in more ecologically relevant situation.

-Because no dominance can be originally claimed, dyadic encounter in neutral places evokes a mix of offensive-defensive and flight behaviors, rarely seen in the home cage confrontation [START_REF] Olivier | Social behaviour in rats and mice: an ethologically based model for differentiating psychoactive drugs[END_REF]. Within two rats living in the same home cage, quantification of dominance behaviors is based on the individual identified as making the largest number of 'pins' (when the dominant rat pushes the other rat over and holding it down with its front paws) and dominance grooming or pouncing aimed at the hindquarters where a rat attempts to leap onto its congener [START_REF] Blanchard | Subordination stress: behavioral, brain, and neuroendocrine correlates[END_REF]. However, in dyadic encounter, attention of an individual is mainly directed or even restricted to the encountered partner [START_REF] Grant | An analysis of the social behaviour of the male laboratory rat[END_REF].

-In tetradic encounter, direct agonistic confrontations are attenuated by the presence of other individuals and the rat is no longer forced to direct its attention to one counter-partner (Wolffgramm, 1990b).

There is little fighting within a colony [START_REF] Barnett | An analysis of social behaviour in wild rats[END_REF] and dominance is often maintained through more discrete behaviors.

-Because rodents heavily rely on their sense of smell to explore their environment and because body odors provide essential information about the social status of conspecifics (for review see [START_REF] Brown | Mammalian social odors: a critical review[END_REF], sniffing behavior also serves to transmit the social hierarchy. Indeed, it has been shown that sniffing is a signal of appeasement during social interactions and that rats showing more agonistic behaviors explore their submissive congeners much more than the other way around [START_REF] Wesson | Sniffing behavior communicates social hierarchy[END_REF] suggesting that quantification of sniffing behavior can inform the social hierarchy of the group.

-The competitive task for a resource [START_REF] Syme | An analysis of the limited access measure of social dominance in rats[END_REF][START_REF] Malatyńska | The effect of antidepressant drugs on dominance behavior in rats competing for food[END_REF] consists in conditioning the rat to have access to a reward (i.e. a bottle of sugar water) when alone. Once the habituation phase is over, all the animals of the same social group are placed together in the experimental arena and the time spent by each animal to drink from the sugar water bottle is measured. The rats having spent the most time drinking are considered dominant, the others, subordinate.

-The cylinder test is also classically used [START_REF] Lindzey | Social dominance in inbred mouse strains[END_REF][START_REF] Messeri | Dominance behavior: a phylogenetic analysis in the mouse[END_REF]. The test consists of a cylinder with a diameter matching the size of the animal, so that, once entered the tube, the animal cannot turn around. An animal is positioned at each end and the dominant is determined as the one having passed through the whole tube, forcing his congener to move back.

Social hierarchy emerges from the interplay between the costs and benefits of agonistic behaviors and social dominance may results from a higher valuation of the benefits or lower valuation of the cost. In fact, rats selectively bred for low saccharin intake are subordinate to high-saccharin-consuming rats when they compete in weight-matched dyads for food [START_REF] Eaton | Sweet success, bitter defeat: a taste phenotype predicts social status in selectively bred rats[END_REF]. Even engaging in offensive aggressive behaviors and winning a fight is highly reinforcing [START_REF] Grant | An analysis of the social behaviour of the male laboratory rat[END_REF][START_REF] Golden | Compulsive Addiction-like Aggressive Behavior in Mice[END_REF] and therefore support additional incentive for the maintenance of social dominance. On the other hand, social hierarchy has been linked to a more general coping strategy to stress (for review see [START_REF] Koolhaas | Individual variation in coping with stress: a multidimensional approach of ultimate and proximate mechanisms[END_REF] with dominant individuals being more resilient to stress, and prone to proactive behaviors such aggressive and impulsive/risk taking behavior (for reviews see [START_REF] Koolhaas | Coping style and immunity in animals: making sense of individual variation[END_REF][START_REF] Cooper | Neurobiological Mechanisms Supporting Experience-Dependent Resistance to Social Stress[END_REF].

The translational value of these experiments should be apprehended with caution as the relationship between stress and the social status is greatly dependent on the group context. Indeed, most studies are conducted in laboratory captive colonies of rodents, where subordinate individuals cannot leave the group and exhibit a higher level of glucorticorticoids (GCs), an index of stress (for review see [START_REF] Creel | Social dominance and stress hormones[END_REF]. In group-housed monkeys, social subordination is stressful [START_REF] Kaplan | Adrenal responsiveness and social status in intact and ovariectomized Macaca fascicularis[END_REF][START_REF] Shively | Social subordination stress, behavior, and central monoaminergic function in female cynomolgus monkeys[END_REF], consistent with findings in humans suggesting a relationship between socioeconomic status, social conditions, and susceptibility to disease (for review see [START_REF] Adler | Health psychology: Why do some people get sick and some stay well?[END_REF][START_REF] Krantz | Effects of psychological and social factors on organic disease: a critical assessment of research on coronary heart disease[END_REF]. However, in the wild, dominant individuals, that have to constantly ascertain their status, have higher levels of GCs than subordinates (for review see [START_REF] Creel | Social dominance and stress hormones[END_REF].

The influence of social status on drug use has only been conducted in captive colony for obvious technical reasons. In accordance with the effect of social defeat on drug use, subordinate rats drink more alcohol or opiates than dominant rats [START_REF] Blanchard | Social structure and ethanol consumption in the laboratory rat[END_REF]Wolffgramm, 1990a;[START_REF] Wolffgramm | Social behavior, dominance, and social deprivation of rats determine drug choice[END_REF][START_REF] Heyne | The development of opiate addiction in the rat[END_REF]. These studies concords with studies on monkeys in captive colonies showing increased alcohol self-administration of subordinates [START_REF] Helms | Social rank, chronic ethanol selfadministration, and diurnal pituitary-adrenal activity in cynomolgus monkeys[END_REF]. However, when rats have exacerbated intake and show signs of "behavioral dependence", social factors are no longer relevant [START_REF] Wolffgramm | Social behavior, dominance, and social deprivation of rats determine drug choice[END_REF][START_REF] Heyne | The development of opiate addiction in the rat[END_REF]. The role of the social status on drug use is not even clear during the early stage. In contrast to the predisposition of subordinates to alcohol use, dominant rats identified according to their behaviors during the competitive access to milk shake reward, maintain higher rates of cocaine self-administration but show no differences in the acquisition, extinction and reinstatement of this behavior [START_REF] Jupp | Social dominance in rats: effects on cocaine self-administration, novelty reactivity and dopamine receptor binding and content in the striatum[END_REF]. Such inconsistency could result from the mean of selecting dominant and subordinate animals or from the fact that the effect of the social status on drug use depend on the subjective effect of the drug (sedative alcohol or opiates vs stimulant cocaine). In addition to the drug considered, environmental context is another factor to consider. In standard condition, selectively bred socially-dominant mice (Dom) show cocaineinduced place preference, while selectively bred submissive mice display a cocaine conditioned place aversion to the drug. However, following a 4-week regimen of Chronic Mild Stress, submissive mice display a marked increase in cocaine CPP, but this regimen has little effect on the cocaine CPP of dominant mice [START_REF] Yanovich | Social rank-associated stress vulnerability predisposes individuals to cocaine attraction[END_REF]. As for today, the role of the social status on drug use thus remains difficult to define.

Contact with drug experienced peer in the home-cage predispose to drug use.

The distal influence of the social context does not always protect from drug use. In fact, animal housed with experienced animals favor the development of drug use. Social transmission of alcohol use has been demonstrated in rodents (for review see [START_REF] Strickland | The effects of social contact on drug use: behavioral mechanisms controlling drug intake[END_REF]. Even animals housed with peer that passively experienced alcohol are predisposed to consume alcohol [START_REF] Fernández-Vidal | Socially mediated alcohol preferences in adolescent rats following interactions with an intoxicated peer[END_REF]). Similar results have been observed with animals housed with cocaine experienced peers. Rats housed with cocaine experienced peers demonstrate a greater escalation of cocaine intake than rats paired with a drug naïve partner [START_REF] Robinson | The effects of social contact on cocaine intake under extended-access conditions in male rats[END_REF]. The social transmission of food preference is mediated by olfactory cues passing from demonstrator to observer, providing observers with information concerning demonstrators' diets and that these olfactory cues are sufficient to bias diet selection by observers [START_REF] Galef | Transfer of information concerning distant foods: A laboratory investigation of the "information-centre" hypothesis[END_REF]. It is tempting to suggest the same process likely occurs during the social transmission of alcohol intake. However, the intravenous route of cocaine self-administration renders socially transmitted cocaine through olfactory cues unlikely.

Proximal social factors and drug use

Social interactions are rewarding and can overcome drug reward

As mentioned above, social life has many advantages in terms of reproduction, defense, foraging and even survival. However, individuals of the group do not likely draw the advantages of social living. Instead groups are formed because social interaction are inherently rewarding. Positive social interactions, like other types of reward, generate a positive feeling, facilitate learning and approach behaviors towards associated stimuli (for review see [START_REF] Trezza | Evaluating the rewarding nature of social interactions in laboratory animals[END_REF]. In rodents, social interactions between adults and specialized social behavior between adults and young, such as maternal behavior or between young such as social play are strong incentive in rodents. Adults rats develop a preference for a compartment associated with non-aggressive social interactions [START_REF] Douglas | Rewarding properties of social interactions in adolescent and adult male and female rats: impact of social versus isolate housing of subjects and partners[END_REF] and cross an elevated T maze to gain access to a partner [START_REF] Werner | Opportunity for interaction as reinforcement in a 'T'maze[END_REF].

Recent studies of pro-social behavior in rats have also demonstrated that rats are able to release a trapped rat from a restraint tube (Ben-Ami [START_REF] Bartal | Empathy and pro-social behavior in rats[END_REF][START_REF] Hachiga | Does a rat free a trapped rat due to empathy or for sociality?[END_REF]. Similarly, mothers develop a preference for a compartment previously associated with pups [START_REF] Fleming | Rat pups are potent reinforcers to the maternal animal: Effects of experience, parity, hormones, and dopamine function[END_REF][START_REF] Panksepp | Social reward among juvenile mice[END_REF] and lever press to gain access to pups [START_REF] Hauser | Lever pressing for pups: evidence for hormonal influence upon maternal behavior of mice[END_REF] [START_REF] Lee | Mother rats bar-press for pups: effects of lesions of the mpoa and limbic sites on maternal behavior and operant responding for pupreinforcement[END_REF]. Finally, adolescent rats develop a preference for social interaction [START_REF] Douglas | Rewarding properties of social interactions in adolescent and adult male and female rats: impact of social versus isolate housing of subjects and partners[END_REF] and lever press to gain the opportunity to interact with same-age congeners [START_REF] Ikemoto | The effects of early social isolation on the motivation for social play in juvenile rats[END_REF]. In fact, adolescent rats prefer a compartment where they previously experience social play at the expense of another compartment where they previously experienced interaction with a partner rendered unresponsive to play solicitations [START_REF] Calcagnetti | Place conditioning reveals the rewarding aspect of social interaction in juvenile rats[END_REF]. In the adults, we have shown that only the dominant rats exhibit a place preference for a compartment associated with the social presence of the home-cage partner (Giorla et al., 2018).

Social reward in rodents can overcome drug reward. Rats prefer a compartment previously paired with social interaction between gender-and weight matched male conspecific at the expense of a compartment previously paired with cocaine [START_REF] Kummer | Differences in social interaction-vs. cocaine reward in mouse vs. rat[END_REF] or amphetamine [START_REF] Yates | Concurrent choice for social interaction and amphetamine using conditioned place preference in rats: effects of age and housing condition[END_REF]. In addition, pairing the compartment with social interaction in rats prevents the reinstatement of the preference for a compartment associated with cocaine (Fritz et al., 2011a). The option for social interaction suppresses the choice for methamphetamine even in rats that meet criteria for addiction [START_REF] Venniro | Volitional social interaction prevents drug addiction in rat models[END_REF]. Similarly, the incentive salience of pups for mothers can exceed that of cocaine during the early postpartum period [START_REF] Mattson | Comparison of two positive reinforcing stimuli: pups and cocaine throughout the postpartum period[END_REF][START_REF] Mattson | Preferences for cocaine-or pup-associated chambers differentiates otherwise behaviorally identical postpartum maternal rats[END_REF][START_REF] Seip | Increasing the incentive salience of cocaine challenges preference for pup-over cocaine-associated stimuli during early postpartum: place preference and locomotor analyses in the lactating female rat[END_REF][START_REF] Pereira | The medial preoptic area is necessary for motivated choice of pup-over cocaine-associated environments by early postpartum rats[END_REF]. This parallels clinical studies showing that drug addicted women decrease their cocaine use during late pregnancy and lactation (for reviews see [START_REF] Chapman | Substance Use among Adolescent Mothers: A Review[END_REF], and are more likely to ask for help to stop using drugs.

However, few studies have demonstrated the inability of social interaction to distract from drug use. [START_REF] Kummer | Differences in social interaction-vs. cocaine reward in mouse vs. rat[END_REF] show that mice have a clear preference for the compartment associated with a moderate dose of cocaine over the compartment paired with social interaction. Also, in the 'rescue' paradigm, a rescuer rat press a lever to release a rat trapped in a plastic restrainer even at the expense of sucrose self-administration. However, rats with a history of heroin self-administration do not release their cage mate and continue to self-administer heroin (Tomek et al., 2018). It thus appears in these conditions that a familiar peer in distress does not divert from seeking heroin. Such models are arguably of high translational significance for the situation of the human addict.

In these procedures, the protective role of social interaction as an alternative reinforcement on drug use, at least at early stages, may likely relate to the ability of social interaction to distract from drug use. However, the effect of social interaction on drug abuse greatly depends on the nature and quality of an individual's social group. For example, a good predictor of teen drug use is determined by the drug use of the group of friends (for review see [START_REF] Kandel | Drug and drinking behavior among youth[END_REF]. Of course, adolescents who use drugs tend to choose friends who use drugs, but longitudinal data indicate that the effect of drug user peers and the choice for drug user peers on the use of drug are about equal in strength [START_REF] Kandel | Drug and drinking behavior among youth[END_REF]. Nevertheless, the peer pressure to take drugs seems to be true when the actors are adolescent and especially when they all have access to the drugs. In this situation, the promoting effect of proximal social interaction on drug use happened when peers are present during the first drug experiences. In this situation, peers can be an incentive to use drug, potentiate (or repress) the rewarding effect of drugs, act as a demonstrator sustaining imitation learning of drug use or act as discriminatory stimulus for drug use. More detailed analyses of what modulates drug intake in case of peer presence is important to address the few studies that have investigated these issues to date.

Presence of an abstaining peer

The direct influence of peer presence on drug self-administration has shown different results that may be due to differences in the experimental conditions. Rats drink more from an ethanol sipper when the sipper predict social contact with a same sex peer [START_REF] Tomie | Effects of ethanol sipper and social opportunity on ethanol drinking in rats[END_REF] suggesting that social interaction can act as an incentive for drug use. In adolescent rats, cocaine or nicotine CPP is increased by the presence of a peer, suggesting that a peer increases the affective valence of drug use [START_REF] Thiel | Social reward-conditioned place preference: a model revealing an interaction between cocaine and social context rewards in rats[END_REF][START_REF] Thiel | Synergistic interaction between nicotine and social rewards in adolescent male rats[END_REF]. On operant behavior, the presence of a peer separated by a Plexiglas panel facilitates amphetamine self-administration at a high dose, but not at a low dose in single-housed adult rats [START_REF] Gipson | Social facilitation of d-amphetamine self-administration in rats[END_REF]. In similar condition using a Plexiglas divider, the same effect has been observed for nicotine [START_REF] Chen | Social interaction promotes nicotine selfadministration with olfactogustatory cues in adolescent rats[END_REF]. Notably, in this latter study, the peer clearly serves as a demonstrator. By transmitting though the holes of the plexiglass divider the olfactogustatory cues associated with the operant response (licking), the demonstrator prompt the observer to imitate the operant behavior. In contrast in [START_REF] Gipson | Social facilitation of d-amphetamine self-administration in rats[END_REF]'s study, the partner is not given the opportunity for operant behavior, more likely representing a discriminative stimulus for drug availability for the selfadministering rat. In fact, a recent study shows that a peer previously present during acquisition of cocaine self-administration can be used as a discriminative cue to induce reinstatement after extinction [START_REF] Weiss | Social reinstatement: a rat model of peer-induced relapse[END_REF].

In contrast to the facilitating effect of peer presence on drug use, rats reduce cocaine self-administration in the presence, through a grid, of an abstaining rat, naïve to cocaine [START_REF] Smith | Peer influences on drug self-administration: social facilitation and social inhibition of cocaine intake in male rats[END_REF]. The ability of the peer to distract from self-administrating the drug seems to depends on the animal receptivity to the partner. Indeed, as female rats are more receptive to males during proestrus, the presence of a male greatly distract from cocaine and heroin self-administration during this period while males are minimally influenced by the hormonal status of a female partner (Lacy et al., 2016). We also observed the similar reducing effect of the presence of an observing peer separated by a grid on cocaine intake in male adult rats. Interestingly, our rat study paralleled our human study based on questionnaires regarding the last episodes of drug consumption and the presence of peers in groups or dyads and found similar beneficial effect of social presence at reducing drug intake in both rats and humans [START_REF] Giorla | Of Rats And Men: Peer Presence And Familiarity Are Key Factors Which Reduce Drug Intake[END_REF]. Interestingly, in our procedure, the level of intake decreased the most when the peer was naïve to the drug [START_REF] Giorla | Of Rats And Men: Peer Presence And Familiarity Are Key Factors Which Reduce Drug Intake[END_REF], suggesting that the behavior towards the drug of the congener is also an important factor to evaluate.

Presence of a peer also consuming

The transmission of drug related states amongst peers seems important in the valuation of the drug. The CPP induced by methamphetamine is greater when two mice share the same drug-experience relative to when a mouse is conditioned together with a "sober congener" [START_REF] Watanabe | Drug-social interactions in the reinforcing property of methamphetamine in mice[END_REF][START_REF] Watanabe | Common experience modifies the reinforcing properties of methamphetamine-injected cage mates but not morphine-injected cage mates in C57 mice[END_REF]. Also, previous morphine experiences with morphine experiencing peers increases the ability to acquire CPP induced by high dose of morphine (20mg/Kg subcutaneously) when they are conditioned alone. This suggest that peer co-experiencing drug promote the rewarding effect of drug use. However, the presence of peers that share the same experience of morphine has been shown to prevent the acquisition of CPP induced by a low dose of morphine (1mg/Kg, intraperitoneally) in adults mice [START_REF] Watanabe | Social factors in conditioned place preference with morphine in mice[END_REF][START_REF] Watanabe | Common experience modifies the reinforcing properties of methamphetamine-injected cage mates but not morphine-injected cage mates in C57 mice[END_REF]. The co-experience of low to moderate doses of morphine (0.25 to 5 mg/Kg subcutaneously) also prevents the acquisition of the morphine CPP in adolescent mice from the social bl/C57 but not from relatively less social BALB/C strains [START_REF] Kennedy | Social influences on morphineconditioned place preference in adolescent BALB/cJ and C57BL/6J mice[END_REF].The contrasting effect of social proximal effect on drugs of different classes parallels clinical and preclinical studies showing the predominant use of stimulant in outdoor social environment while the use of opiates is predominantly solitary and indoor (for review see [START_REF] Badiani | Role of environmental factors in cocaine addiction[END_REF].

Experiments using drug self-administration have also shown various effects. As discussed before, social group are less prone to use drug than isolated animals. However, [START_REF] Logue | Adolescent mice, unlike adults, consume more alcohol in the presence of peers than alone[END_REF] observed that male adolescent, but not female or adult, C57BL/6J mice consume more alcohol when housed in group than when isolated. Siblings of prairie voles, a highly sociable rodents, exhibit greater preference for ethanol over water when housed together, than housed separately [START_REF] Anacker | Prairie voles as a novel model of socially facilitated excessive drinking[END_REF].

In non-human primates, it has been shown that rhesus macaques consume more phencyclidine in the presence of a congener that has also access to the drug [START_REF] Newman | Social stimuli enhance phencyclidine (PCP) selfadministration in rhesus monkeys[END_REF]. Similarly, rats allowed to interact through a grid during acquisition of cocaine self-administration take more cocaine if both have access to cocaine than if only one rat has access to it [START_REF] Smith | Peer influences on drug self-administration: social facilitation and social inhibition of cocaine intake in male rats[END_REF][START_REF] Peitz | Peer influences on drug self-administration: an econometric analysis in socially housed rats[END_REF]. In the same procedure, rats tested with a drug-experienced partner acquire cocaine selfadministration faster and emit more active lever presses than rats tested with a cocaine-naïve partner [START_REF] Smith | The Effects of Social Learning on the Acquisition of Cocaine Self-Administration[END_REF]. Prairie vole drink more alcohol when it is facing the congener on the other side of a mesh-divider than when placed on the other side of the cage [START_REF] Anacker | The role of early life experience and species differences in alcohol intake in microtine rodents[END_REF]. These findings suggest that the behavior of a peer, as opposed to merely the presence of a peer, is the critical factor determining how social presence will affect drug consumption.

In our experiment, rats acquired the self-administration alone and were tested with a peer afterwards. In these conditions, we observed a decreased consumption in presence of the peer. [START_REF] Giorla | Of Rats And Men: Peer Presence And Familiarity Are Key Factors Which Reduce Drug Intake[END_REF].

Altogether, these results suggest the presence of a peer may either predispose drug use through imitation or distract from drug use depending at which stage of drug use the presence of a peer occurs and how receptive the user is to peers. Such complex interactions could explain the different directions that have been observed depending on the matching of drug experience, the sex and the social housing conditions [START_REF] Tomie | Effects of Cagemate Gender and the Cagemate's access to ethanol on ethanol and water intake of the proximal male or the proximal female CD-1 mouse[END_REF][START_REF] Tomie | The Effects of Proximal and Distal Social Stimulation on Ethanol Intake in Male and Female CD-1 Mice[END_REF]. Characterizing the factors that influences these opposing processes are important to understand the effects of peer on drug use. Studies have shown that when the distracting effects of direct physical interaction are removed through plexiglass divider, the stimulating effects of social interaction on ethanol drinking are evident [START_REF] Tomie | Effects of Cagemate Gender and the Cagemate's access to ethanol on ethanol and water intake of the proximal male or the proximal female CD-1 mouse[END_REF][START_REF] Tomie | Effects of number of cagemates on home cage ethanol drinking during proximal cagemate drinking (PCD) procedures in male and female CD-1 mice[END_REF]. Another relevant factor is the familiarity of the congener.

Presence of a stranger or familiar peer and dominance status influence

The social response greatly differs whether the congener is familiar or is a stranger. For instance, pain sensitivity is increased in the presence to a familiar congener similarly in pain but not a stranger congener also experiencing pain [START_REF] Langford | Social modulation of pain as evidence for empathy in mice[END_REF]. Also, the expression of pro-social behavior depends on strain familiarity. When giving the ability to release congener from a restrainer, rats do when the congener is a cage-mate or a same strain stranger (that "looks" like their cage mate) but not when the rats are from a strain they have not been previously paired with (Ben-Ami [START_REF] Bartal | Pro-social behavior in rats is modulated by social experience[END_REF].

The familiarity with the peer also plays a critical role in social modulation of drug use. The greatest facilitation of alcohol drinking is observed when rats interacted with a familiar alcohol-intoxicated and in a lesser extend to a familiar sober rat. In contrast, interaction with an unfamiliar and sober rat reduced drinking. Notably, females do not seem to be sensitive to familiarity [START_REF] Maldonado | Social interaction and partner familiarity differentially alter voluntary ethanol intake in adolescent male and female rats[END_REF]. We have also shown that the presence of an abstaining unfamiliar peer reduces cocaine intake to a larger extent than that of a familiar peer (the cage mate) Interestingly, in our human parallel study, drug users report a lower consumption when in presence of strangers than familiar peers [START_REF] Giorla | Of Rats And Men: Peer Presence And Familiarity Are Key Factors Which Reduce Drug Intake[END_REF].

Also when we tested the influence of a familiar cage mate peer, we found that the dominance status plays a role in the rewarding effect of social interaction. We have shown that the presence of the cage mate is only rewarding in the CPP for the dominant rat [START_REF] Giorla | Of Rats And Men: Peer Presence And Familiarity Are Key Factors Which Reduce Drug Intake[END_REF], in line with a former study in hamsters [START_REF] Gil | Social reward: interactions with social status, social communication, aggression, and associated neural activation in the ventral tegmental area[END_REF]. However, when analyzing the influence of dominance on cocaine self administration in presence of a familiar peer, no significant effect was found (Giorla et al., 2018).

Which sensory modalities are critical for the effect of social modulation of drug use?

Visual stimulation Observing someone can be considered a social reward [START_REF] Anderson | Social stimuli and social rewards in primate learning and cognition[END_REF][START_REF] Deaner | Monkeys pay per view: adaptive valuation of social images by rhesus macaques[END_REF]. The simple observation of an image of a congener also has reinforcing effects in macaques [START_REF] Fujita | Visual preference for closely related species by Sulawesi macaques[END_REF][START_REF] Fujita | Discrimination of macaques by macaques: the case of Sulawesi species[END_REF] and rhesus monkeys spend more time looking at faces than more neutral pictures [START_REF] Wilson | Viewing preferences of rhesus monkeys related to memory for complex pictures, colours and faces[END_REF]. In addition, after training monkeys to use a joystick to view videos of congeners, it has been shown that, in a choice experiment, monkeys prefer to watch videos involving other monkeys rather than having food reward [START_REF] Andrews | Live-social-video reward maintains joystick task performance in bonnet macaques[END_REF].

It is commonly admitted that primates heavily rely on visual stimulus on contrary to rodents. For instance, social play which is highly rewarding in juvenile (for review see [START_REF] Trezza | Evaluating the rewarding nature of social interactions in laboratory animals[END_REF] is not affected by blindness {Siviy, 1987 #276}. However, recent data suggest the role of visual stimulation in rodent social behavior. [START_REF] Watanabe | Preference for and discrimination of videos of conspecific social behavior in mice[END_REF] showed that mice were able to discriminate different behaviors from videos and develop a preference videos showing fight or copulation over sniffing behavior, suggesting a role of visual stimulation in social interaction. It is highly likely that visual stimulation sustains imitation behavior. Visual stimulus seems also to play a key role in "emotional contagion" in mice. Indeed, the hyperalgesia induced by the presence to a familiar but not a stranger congener is mediated through visual rather than olfactory or auditory cues [START_REF] Langford | Social modulation of pain as evidence for empathy in mice[END_REF]. Visual stimulation may also convey the reinforcing effect of social interaction with a familiar peer. Rats learn a novel lever-pressing response that produces access to a familiar partner even if they are only provided visual feedback and physical contact is prevented [START_REF] Angermeier | Some basic aspects of social reinforcements in albino rats[END_REF].

Physical contact

The role of other sensory modalities in social interaction seems also important. Other forms of "emotional contagion" that transfer to both stranger and familiar congener is not mediated by visual but olfactory stimulation [START_REF] Smith | Social transfer of pain in mice[END_REF]. [START_REF] Angermeier | Some basic aspects of social reinforcements in albino rats[END_REF] also showed that rats lever press to access an unfamiliar congener but only if they have contact, even limited, with the new partner.

Consequently, the rewarding effect of or receptivity to familiar vs unfamiliar congener seems to depend on different modalities, with processes directed toward a familiar congener requiring at least visual stimulation while those directed toward an unfamiliar congener requiring physical contact or/and olfactory stimulation.

The critical role of physical contact in social interaction have also been suggested when Wolffgramm (1990b) observed that the effect of isolation resembles those of group housed in cages that limit physical contact, suggesting (Wolffgramm, 1990b). In fact, the most rewarding sensory component of social interaction is physical contact. Even a simple limited contact between rats, through a grid, can induce a CPP [START_REF] Kummer | Conditioned place preference for social interaction in rats: contribution of sensory components[END_REF][START_REF] Peartree | Limited physical contact through a mesh barrier is sufficient for social reward-conditioned place preference in adolescent male rats[END_REF], while visual and auditory stimulation through a plexiglass partition cannot [START_REF] Kummer | Conditioned place preference for social interaction in rats: contribution of sensory components[END_REF]. In juvenile, somatosensory feedback play a key role in the highly rewarding social play as xylocaine anesthesia of the back of the juvenile pairs greatly depresses social play [START_REF] Siviy | Sensory modulation of juvenile play in rats[END_REF].

Unfortunately, apart from this latter study, most of the studies do not dissociate the somatosensory, olfactory or auditory stimulation from physical contact.

Smell

In rodent species, body odors provide essential information about the sex, social and reproductive status of conspecifics [START_REF] Brown | Mammalian social odors: a critical review[END_REF]. Mice explore more a petri dish containing the bedding of their own home cage or that of other mice over empty petri dish or petri dish containing fresh bedding [START_REF] Seillier | Disruption of social cognition in the sub-chronic PCP rat model of schizophrenia: Possible involvement of the endocannabinoid system[END_REF]. Home cage odors support the development of CPP. Notably, only subordinate mice showed CPP to home cage odors [START_REF] Fitchett | There's no place like home: cage odours and place preference in subordinate CD-1 male mice[END_REF]. Olfactory cues also mediate some form of "emotional contagion" [START_REF] Smith | Social transfer of pain in mice[END_REF][START_REF] Laviola | Low empathylike behaviour in male mice associates with impaired sociability, emotional memory, physiological stress reactivity and variations in neurobiological regulations[END_REF] suggesting a role in social communications. In fact, olfactory cues play a key role in social transmission of food preference (for review see [START_REF] Wrenn | Social transmission of food preference in mice[END_REF].

The physiological effects of odors are mediated through the vomeronasal organ and the main olfactory epithelium. Lesions of the main olfactory epithelium by irrigation of the nasal cavity with a solution of zinc sulfate into the nares in males results in a decrease of aggressive behaviors normally directed against unfamiliar males [START_REF] Flannelly | Territorial behavior of laboratory rats under conditions of peripheral anosmia[END_REF] but have limited effect or social play in adolescent [START_REF] Thor | Anosmia and play fighting behavior in prepubescent male and female rats[END_REF] and does not disrupt social sniffing behavior [START_REF] Wesson | Sniffing behavior communicates social hierarchy[END_REF].

Auditory stimulation

Audition play a key role in social play as evidence through ablative procedures. Indeed, deafness greatly suppresses social play in juvenile rats [START_REF] Siviy | Sensory modulation of juvenile play in rats[END_REF]. Results from devocalized rats have shown that vocalizations promote and maintain playful interactions with familiar (Kisko et al., 2015b) but not unfamiliar peers (Kisko et al., 2015a). The role of audition in social behavior of adult rats seems more ambiguous. Adult males are more likely to escalate playful encounters into serious fights when one partner was devocalized (Kisko et al., 2015a) but preventing residents from hearing intruder has no detectable effect on any aggressive behavior. [START_REF] Takahashi | Analysis of ultrasonic vocalizations emitted by residents during aggressive encounters among rats (Rattus norvegicus)[END_REF]. As mentioned above, the hyperalgesia induced by the presence to a familiar but not a stranger congener is not mediated through auditory cues [START_REF] Langford | Social modulation of pain as evidence for empathy in mice[END_REF]. The limited studies using ablative studies is difficult to clearly defined the role of audition in social behaviors despite considerable studies on the auditory communication in rodents. Like all social animals, rats are capable of communication with each other, but also with other species.

Audible vocalizations

First, rats can provide audible squeal sounds of 2 to 4 KHz (for review see [START_REF] Nitschke | Acoustic behavior in the rat: research, theory, and applications[END_REF]. These sounds are cries of alarm, which often express pain or discomfort. They can be emitted to dissuade a predator from approaching (for review see [START_REF] Litvin | Rat 22 kHz ultrasonic vocalizations as alarm cries[END_REF] or to the attention of humans, in anticipation, or during unpleasant treatment or manipulation.

Ultrasonic vocalization (USV)

The natural way of communicating in rats is through the emission of ultrasonic vocalizations (USVs) [START_REF] Burgdorf | Ultrasonic vocalizations of rats (Rattus norvegicus) during mating, play, and aggression: Behavioral concomitants, relationship to reward, and self-administration of playback[END_REF]. But, although researchers had identified the vocalizations of rats in the ultrasound spectrum by the 1960s, their real study only started several years later (for review see [START_REF] Brudzynski | Communication of adult rats by ultrasonic vocalization: biological, sociobiological, and neuroscience approaches[END_REF]. In an experimental setting, UVSs are an effective means of inferring the emotional state of animals (for review see [START_REF] Brudzynski | Ultrasonic calls of rats as indicator variables of negative or positive states: acetylcholine-dopamine interaction and acoustic coding[END_REF].

The vocalizations of adult rats can be classified into two broad categories, according to their frequency of emission. First, vocalizations called "22KHz" reflect a negative emotional state. Rats emit these vocalizations in case of danger or in anticipation of a potentially threatening situation (for review see [START_REF] Brudzynski | Communication of adult rats by ultrasonic vocalization: biological, sociobiological, and neuroscience approaches[END_REF]. These vocalizations are also useful in case of unpleasant stimulus. There are also other situations in which rats will emit 22KHz vocalizations. These include fighting situations [START_REF] Lore | Ultrasounds produced by rats accompany decreases in intraspecific fighting[END_REF], but also during certain sexual contacts [START_REF] Barfield | Sexual behavior: ultrasonic postejaculatory song of the male rat[END_REF]. Although emitted in negative emotional situations, it should be noted that 22KHz vocalizations do not directly express the pain of animals. Indeed, a rat subjected to an acute pain stimulus ceases to vocalize in these frequencies. These vocalizations are associated with the anxiety created by these painful stimuli but not with the pain itself [START_REF] Jourdan | Analysis of ultrasonic vocalisation does not allow chronic pain to be evaluated in rats[END_REF].

The second major class of USVs, called "50KHz", reflects a positive emotional state for the rat. Positive vocalizations are much more heterogeneous than negatives and are divided into several categories, based on the profile of their frequency and duration (for review see [START_REF] Brudzynski | Pharmacology of Ultrasonic Vocalizations in adult Rats: Significance, Call Classification and Neural Substrate[END_REF]. Firstly, they can be separated into "flat" vocalizations (flat, FL), ie the frequency of the vocalization emitted remains constant throughout the duration of the emission, or else at " frequency modulated " (FM, ie the frequency is modulated during the duration of the transmission of the vocalization). The two types, FL and FM, however, have the same peak frequency, between 45 and 55KHz. Regarding the duration of vocalization, the 50KHz FL have a duration of about 10-100ms and their frequency range can range from 35 to 50KHz. The 50KHz FM have a longer duration, since they can last from 20 to 150ms and their frequency range is between 40 and 80KHz [START_REF] Wohr | Effects of experience and context on 50-kHz vocalizations in rats[END_REF][START_REF] Takahashi | Structure of rat ultrasonic vocalizations and its relevance to behavior[END_REF].These vocalizations are also called "social vocalizations" and are expressed in positive or neutral contexts (ie non-aggressive, non-aversive or "friendly") such as sexual contact or the expectation of interaction with a congener [START_REF] Bialy | Precontact 50-kHz vocalizations in male rats during acquisition of sexual experience[END_REF]. The emission of positive USVs is also related to the anticipation and / or the search for social interactions. Rats exploring environments frequently occupied by other rats, even in their absence emit positive vocalizations [START_REF] Brudzynski | Social contacts and production of 50-kHz short ultrasonic calls in adult rats[END_REF]. The authors have further shown that the amount of vocalization emitted is proportional to the number of individuals having occupied this space. Rats also emit vocalizations of pleasure in anticipation of a certain number of rewards. Indeed, it has been shown that rats emit more 50KHz vocalization in anticipation of electrical stimulation of the ventral tegmental area [START_REF] Burgdorf | Anticipation of rewarding electrical brain stimulation evokes ultrasonic vocalization in rats[END_REF]. Although flat and frequency modulated 50KHz vocalizations are issued in positive situations, there is a difference of context in which they are transmitted. Indeed, the 50KHz FM are emitted in very rewarding situations [START_REF] Burgdorf | Frequency-modulated 50 kHz ultrasonic vocalizations: a tool for uncovering the molecular substrates of positive affect[END_REF] whereas the 50KHz FL are identified as having a role of social coordination and serve as vocalizations of contact [START_REF] Wohr | Effects of experience and context on 50-kHz vocalizations in rats[END_REF]. Finally, some data have shown a dissociation of vocalizations within 50KHz FM. Some vocalizations show rapid frequency oscillations ("trill") while others do not exhibit this characteristic (for review see [START_REF] Brudzynski | Ethotransmission: communication of emotional states through ultrasonic vocalization in rats[END_REF].

There is wide variability in the level of emission of USV. For example, the emission level of USVs varies according to the dominance status. In fact, most of the time, the USVs are emitted by the dominant rat, while the dominated rat emits much fewer vocalizations [START_REF] Thomas | Analysis of ultrasonic vocalizations emitted by intruders during aggressive encounters among rats (Rattus norvegicus)[END_REF]. There are also important individual difference in the propensity to emit positive or negative ultrasonic vocalizations. Tickling rats make them emit positive USVs in some rats. Rats that emit the most positive USVs make more risky decision in ambiguous situation [START_REF] Rygula | Laughing rats are optimistic[END_REF].

Ultrasonic vocalization and drug addiction.

Rats emits 50KHz USVs to the administration or the anticipation of drug that increased over repeated administration (for review see [START_REF] Barker | Ultrasonic Vocalizations as a Measure of Affect in Preclinical Models of Drug Abuse: A Review of Current Findings[END_REF]. Notably, the type of emission over the course of self-administration change across time starting with trills with flat after more extended self-administration history. This suggest change in valuation of drug over the course of drug history [START_REF] Maier | The missing variable: ultrasonic vocalizations reveal hidden sensitization and tolerance-like effects during long-term cocaine administration[END_REF]. This parallel tolerance of the hedonic effect of the drug over the course of drug taking history. On the other hand, withdrawal from drug use evoke 22kHz negative ultrasonic vocalizations (for review see [START_REF] Barker | Ultrasonic Vocalizations as a Measure of Affect in Preclinical Models of Drug Abuse: A Review of Current Findings[END_REF].

Communications of such affective appraisal among a group remains elusive but the function of USV has been demonstrated in USV replay studies [START_REF] Brudzynski | Behavioural responses of laboratory rats to playback of 22 kHz ultrasonic calls[END_REF]. Positive 55 kHz ultrasonic vocalizations are rewarding. Rats approach playback of 55 kHz ultrasonic vocalizations [START_REF] Wohr | Ultrasonic communication in rats: can playback of 50-kHz calls induce approach behavior[END_REF] and lever press for them [START_REF] Burgdorf | Ultrasonic vocalizations of rats (Rattus norvegicus) during mating, play, and aggression: Behavioral concomitants, relationship to reward, and self-administration of playback[END_REF]. In contrast, rats hearing negative 22 kHz show fight/flight/freeze stress responses [START_REF] Sales | The effect of 22 kHz calls and artificial 38 kHz signals on activity in rats[END_REF][START_REF] Brudzynski | Behavioural responses of laboratory rats to playback of 22 kHz ultrasonic calls[END_REF][START_REF] Beckett | Pharmacological manipulation of ultrasound induced defence behaviour in the rat[END_REF][START_REF] Commissaris | Acoustically elicited behaviours in Lister hooded and Wistar rats[END_REF].

In a recent study, we have shown that the playback of positive USV of a nonfamiliar rat can reduce cocaine intake [START_REF] Montanari | Subthalamic nucleus mediates the modulation on cocaine self-administration induced by ultrasonic vocalization playback in rats[END_REF]. This mirror our previous study showing that presentation of an unfamiliar peer after acquiring selfadministration alone induce positive ultrasonic vocalization and reduce self-administration [START_REF] Giorla | Of Rats And Men: Peer Presence And Familiarity Are Key Factors Which Reduce Drug Intake[END_REF]. In contrast, play back of negative USV transiently increase self-administration [START_REF] Montanari | Subthalamic nucleus mediates the modulation on cocaine self-administration induced by ultrasonic vocalization playback in rats[END_REF]. These results highlight the critical role of vocal communication in the influence of proximal social factors on drug consumption.

Neurobiological substrate of social influence on drug use

Distal social factors

The neurobiology of social influence has been extensively assessed for distal social factors such as play behavior (for review see [START_REF] Vanderschuren | The neurobiology of social play behavior in rats[END_REF]. Here we will critically review their main conclusions and discussed the role of some less studied substrata of social behaviors. Generally, studies on neural basis of social behaviors have highlighted the role of dopamine and opioid systems in this rewarding behavior, but also the cholinergic system for its involvement in the attentional processes required for social interactions. Distal social influences such as social rearing context (maternal separation, isolation) act as stressors and have been shown to affect the serotoninergic, dopaminergic and opioid systems, as well as the hypothalamic-pituitary-adrenal axis (for review see [START_REF] Bardo | Individual differences and social influences on the neurobehavioral pharmacology of abused drugs[END_REF]. The roles of these neurotransmitters and neuromodulators are not restricted to social stimuli, more likely sustaining or repressing the hedonic/rewarding functions of the nucleus accumbens, arousing functions of the hypothalamus and/or prefrontal executive functions in response to social stimuli or the lack of them.

In contrast, while the neuropeptide oxytocin reduces more generally anxiety, potentially affecting social performance, it seems to act more specifically on social behaviors mainly enhancing affiliative prosocial behaviors or regulates cooperation and conflict among humans in the context of intergroup relations (for review see Shamay-Tsoory and Abu-Akel, 2016). Similarly, oxytocin has a prosocial effect in rodents (for review see [START_REF] Insel | The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior[END_REF]). Yet, accumulating evidence reveals that the effects of OT is context dependant and have on some occasion anti-social effect suggesting, the role in social salience rather than valence (for review see Shamay-Tsoory and Abu-Akel, 2016). Preclinical and clinical studies have demonstrated the ability of oxytocin to reduce intoxication, tolerance to and withdrawal from drugs [START_REF] Bowen | Rebalancing the Addicted Brain: Oxytocin Interference with the Neural Substrates of Addiction[END_REF][START_REF] Pedersen | Oxytocin, Tolerance, and the Dark Side of Addiction[END_REF]. The critical role of oxytocin in the nucleus accumbens, the prefrontal cortex, the central nucleus of the amygdala on various drug-related behaviors using metamphetamine, cocaine, heroin and alcohol has been recently reviewed [START_REF] Leong | Oxytocin and Rodent Models of Addiction[END_REF].

Recent studies on the neuroanatomical basis of the social modulation drug use have push interest further from the "classical" reward system. Amongst them, some have demonstrated that the insular cortex is both implicated in the subjective effect of the drug and involved in prosocial behaviors (for review see [START_REF] Heilig | Time to connect: bringing social context into addiction neuroscience[END_REF].

We and others have also studied the effect of the subthalamic nucleus, the only glutamatergic structure of the basal ganglia that receive direct projection from the prefrontal cortex. Alteration of this structure have opposite effect on food and drug rewards [START_REF] Baunez | The subthalamic nucleus exerts opposite control on cocaine and'natural'rewards[END_REF]. It is also particularly sensitive to the reducing effect oxytocin on methamphetamine induced activation [START_REF] Carson | Systemically administered oxytocin decreases methamphetamine activation of the subthalamic nucleus and accumbens core and stimulates oxytocinergic neurons in the hypothalamus[END_REF] giving it an interesting role in the social modulation of drug use. Extended methamphetamine reduced oxytocin receptor density in the nucleus accumbens and the subthalamic nucleus (Baracz et al., 2016b), suggesting a modulatory effect of drug on oxytocin. In addition, injection of oxytocin in the nucleus accumbens core or in the subthalamic nucleus (STN) reduces reinstatement of metamphetamine seeking behavior [START_REF] Baracz | The involvement of oxytocin in the subthalamic nucleus on relapse to methamphetamine-seeking behaviour[END_REF]Baracz et al., 2016a) and reduces ethanol intake when injected intracerebroventricularly [START_REF] Peters | Oxytocin inhibits ethanol consumption and ethanol-induced dopamine release in the nucleus accumbens[END_REF], suggesting a role of oxytocin on drug use. The mechanisms by which oxytocin could affect the drug-related behaviors is hypothesized to be a facilitating effect of oxytocin on the rewarding effects of prosocial behaviour at the expense of drug-related rewards [START_REF] Leong | Oxytocin and Rodent Models of Addiction[END_REF]. Nevertheless, the studies carried out in this context do not make it possible to know what are the neurobiological mechanisms and the cerebral structures involved in the influence of the distal social factors on the phenomena of addiction.

Proximal social factors

There is to date no published study assessing directly the neurobiology of proximal social factors during drug consumption. Studies offering the choice between social reward and drug reward have assessed neurobiological substrate. One study has shown that rats choosing between the social reward and cocaine reward in a CPP paradigm have a level of oxytocin expression in the paraventricular nucleus of hypothalamus intermediate between animals experiencing only one of the two rewards [START_REF] Liu | Neuronal activity and the expression of hypothalamic oxytocin and vasopressin in social versus cocaine conditioning[END_REF]. With the same procedure, inactivation of the core of the nucleus accumbens or the BLA shift the CPP away from cocaine toward social interaction while lesioning the AcbSh produced the opposite effect (Fritz et al., 2011b). In the study assessing the choice between volitional social reward and methamphetamine or heroin, an increased inhibitory activity in the central amygdala and inhibition of the anterior ventral insular cortex have been shown to be critical for the influence of social reward access at diminishing incubation [START_REF] Venniro | Volitional social interaction prevents drug addiction in rat models[END_REF]. In the rescue paradigm where social interaction does not detract from drug use, the neurobiological substrate has not yet been investigated (for review see Tomek and Olive, 2018). Since both reward and emotion processes are involved when a peer is present during drug consumption, we could hypothesize that the prefrontal cortex and the amygdala should be involved. Given what has been reported on the role of oxytocin on prosocial behaviours and the influence of oxytocin when injected in the STN (see above), we have however investigated the effects of lesions of the STN in the influence of presence of a peer on cocaine intake. The STN is part of the basal ganglia and has been shown to regulate motivation. Indeed, lesions or high frequency deep brain stimulation of the STN decrease motivation for cocaine, while increasing that for sweet food [START_REF] Baunez | The subthalamic nucleus exerts opposite control on cocaine and'natural'rewards[END_REF][START_REF] Rouaud | Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation[END_REF] and prevent escalation or reescalation of cocaine, heroin or alcohol intake [START_REF] Pelloux | Targeting the subthalamic nucleus in a preclinical model of alcohol use disorder[END_REF][START_REF] Wade | High-frequency stimulation of the subthalamic nucleus blocks compulsive-like re-escalation of heroin taking in rats[END_REF][START_REF] Pelloux | Subthalamic nucleus high frequency stimulation prevents and reverses escalated cocaine use[END_REF]. In another hand, STN lesions have also been shown to blunt affective responses to sweet or bitter solutions and to alcohol [START_REF] Pelloux | The subthalamic nucleus keeps you high on emotion: behavioral consequences of its inactivation[END_REF][START_REF] Pelloux | Targeting the subthalamic nucleus in a preclinical model of alcohol use disorder[END_REF]. We have tested the effects of STN excitotoxic lesions in rats self-administering cocaine in presence of an abstaining familiar or unfamiliar peer. STN lesions reduced the drug intake, but abolished the difference between familiar and unfamiliar peer (Giorla et al, data unpublished). In the experiment testing the effects of USV playback on cocaine intake, STN lesions blocked the influence of USV and cocaine intake remained stable [START_REF] Montanari | Subthalamic nucleus mediates the modulation on cocaine self-administration induced by ultrasonic vocalization playback in rats[END_REF].

These recent experiments highlight a critical role of STN at mediating the influence of proximal social factors on drug intake. Further studies will be necessary to identify the entire network involved in these effects.

Conclusion

Understanding the modulation of social factors to drug use and drug addiction is important to improve prevention strategy for the initiation and maintenance of drug use and particularly in teenager who are particularly both vulnerable to drugs and sensitive to their peer. It is also important for adult drug addicted individuals for whom social context can either promote or prevent relapse. The social context (familiarity, experience with drugs of the congeners), substance seem to be important factors that may be critical to take into account. Many other factors remain to be investigated. A better understanding of the neurobiological substrate of these influences is necessary and only few studies have investigated this issue. The potential translation to human drug users is highly valuable and could lead to better reduction harm policies and possible future treatment strategies.

Acknowledgements and Disclosure: Our research was funded by CNRS, Aix-Marseille Université (AMU), the "Agence Nationale pour la Recherche" (ANR_2010-NEUR-005-01 in the framework of the ERA-Net NEURON to C.B. and supporting Y.P.), the Fondation pour la Recherche Médicale (FRM DPA20140629789 to C.B.), and the support of the A*MIDEX project (ANR-11-IDEX-0001-02) funded by the "Investissements d'Avenir" French Government program, managed by the French National Research Agency (ANR) to CB and supporting CM. The French ministry for research to EG. The authors have no conflict of interest to declare.