Orexins/Hypocretins: Gatekeepers of Social Interaction and Motivation.

Ever since the discovery of the brain's orexin/hypocretin system, most research was directed toward unveiling its contribution to the normal functioning of individuals. The investigation of reward-seeking behaviors then gained a lot of attention once the distribution of orexinergic neurons was revealed. Here, we discuss findings on the involvement of orexins in social interaction, a natural reward type. While some studies have succeeded in defining the relationship between orexin and social interaction, the controversy regarding its nature (direct or inverse relation) raises questions about what aspects have been overlooked until now. Upon examining the literature, we identified a research gap concerning conditions influencing the impact of orexins on social behavior expression. In this review, we introduce a number of factors (e.g., stress, orexin's source) that must be considered while studying the role of orexins in social interaction. Furthermore, we refer to published research to investigate the stage at which orexins affect social interaction and we highlight the nucleus accumbens (NAc) shell's role in social interaction and other rewarding behaviors. Finally, the underlying orexin molecular pathway influencing social motivation in particular illnesses is proposed. We conclude that orexin's impact on social interaction is multifactorial and depends on specific conditions available at a time.

Social Interaction Is Less Rewarding in Adult Female than in Male Mice.

(1) Background: Positive social relationships are essential for mental and physical health. However, not all individuals experience social interaction as a rewarding activity. (2) Methods: Social interaction reward in mice can be assessed by social conditioned place preference (CPP). The aim of this study is to investigate sex-dependent differences in the neurological underpinnings underlying social versus non-social phenotypes, using adult male and female C57BL/6J mice. (3) Results: Adult female mice expressed significantly less social reward than males from the same strain. Accordingly, pairs of male mice spent more time interacting as compared to female pairs. Subsequently, we analyzed neuropeptides previously reported to be important regulators of social behavior such as oxytocin, vasopressin, and orexin, in addition to Ca2+/calmodulin-dependent protein kinase II (αCaMKII), shown to be involved in social reward. Levels of neuropeptides and αCaMKII were comparable between males and females in all investigated regions. Yet, a significant negative correlation was found between endogenous oxytocin expression and social reward in female pairs. (4) Conclusions: Sex differences in the prevalence of many mental health disorders might at least in part be due to sex differences in social reward. Therefore, more research is needed to unravel the candidate(s) underlying this behavioral difference.

Protein kinases in natural versus drug reward.

Natural and drug rewards act on the same neural pathway, the mesolimbic dopaminergic system. In brain regions such as the nucleus accumbens and ventral tegmental area, drugs of abuse-induced stimulation of signaling pathways can lead to synaptic reshaping within this system. This is believed to be underlying the maladaptive alterations in behaviors associated with addiction. In this review, we discuss animal studies disclosing the implication of several protein kinases, namely protein kinase A (PKA), extracellular signal regulated kinase (ERK) mitogen-activated protein kinases (MAPK), p38 MAPK, and calcium/calmodulin-dependent kinase II (CaMKII), in reward-related brain regions in drug and natural reward. Furthermore, we refer to studies that helped pave the way toward a better understanding of the neurobiology underlying non-drug and drug reward through genetic deletion or brain region-specific pharmacological inhibition of these kinases. Whereas the role of kinases in drug reward has been extensively studied, their implication in natural reward, such as positive social interaction, is less investigated. Discovering molecular candidates, recruited specifically by drug versus natural rewards, can promote the identification of novel targets for the pharmacological treatment of addiction with less off-target effects and being effective when used combined with behavioral-based therapies.

The Anti-social Brain in Schizophrenia: A Role of CaMKII?

Current pharmacological therapy has limited effects on the cognitive impairments and negative symptoms associated with schizophrenia. Therefore, understanding the molecular underpinnings of this disorder is essential for the development of effective treatments. It appears that a reduction in calcium/calmodulin-dependent protein kinase II (α-CaMKII) activity is a common mechanism underlying the abnormal social behavior and cognitive deficits associated with schizophrenia. In addition, in a previous study social interaction with a partner of the same sex and weight increased the activity of α-CaMKII in rats. Here, we propose that boosting of CaMKII signaling, in a manner that counteracts this neuropsychiatric disease without disrupting the normal brain function, might ameliorate the abnormalities in social cognition and the negative symptoms of schizophrenia.

Implication of Extracellular Signal-Regulated Kinase in the Expression of Natural Reward: Evidence Not Found.

Many studies have implicated extracellular signal-regulated kinase (ERK) in drug-rewarding properties. Yet, only few investigated whether ERK also mediates the naturally rewarding stimuli. In this study, we compared ERK activation in the nucleus accumbens (NAc) after cocaine reward and after positive social interaction (SI) with a partner-reward in male rats. With our protocol, ERK phosphorylation in the NAc was not increased after cocaine reward. In addition, the interaction with a social partner did not alter ERK activation in the NAc. These results suggest that ERK in the NAc may not be involved in natural reward learning. SI in an alternative context to the one associated with drugs of abuse can abolish drug preference. Given that intra-NAc core ERK inhibition impaired the expression of cocaine preference, we wanted to investigate whether the protective effects of SI when an individual is allowed to interact with a social partner in an alternative context to the one associated with drugs during the learning phase are enhanced by ERK inhibition. For that, U0126 was bilaterally infused into the NAc core of rats conditioned with cocaine in one context and with SI in the opposite context before assessing the expression of reward-related learning. Intra-NAc core ERK inhibition was ineffective to impair the expression of drug reward as previously demonstrated, when a social partner was available in an alternative context. Thus, the effects of the pharmacological manipulations based on decreasing ERK activity are not cumulative to other treatments for drug addiction based on SI.

Rewarding Social Interaction in Rats Increases CaMKII in the Nucleus Accumbens.

Calcium/calmodulin-dependent protein kinase II (CaMKII) is known to be involved in the sensitized locomotor responses and drug-seeking behavior to psychostimulants. However, little is known about the contribution of CaMKII signaling in the nucleus accumbens (NAc) in natural rewards such as social interaction. The present experiments explored the implication of CaMKII signaling in drug versus natural reward. In the NAc of rats expressing cocaine or social interaction conditioned place preference (CPP), αCaMKII activation was induced in those expressing social interaction but not cocaine CPP. In order to investigate the role of NAc CaMKII in the expression of reward-related learning of drug versus non-drug stimuli, we inhibited CaMKII through an infusion of KN-93, a CaMKII inhibitor, directly into the NAc shell or core, before the CPP test in a concurrent paradigm in which social interaction was made available in the compartment alternative to the one associated with cocaine during conditioning. Whereas vehicle infusions led to equal preference to both stimuli, inhibition of CaMKII by a KN-93 infusion before the CPP test in the shell but not the core of the NAc shifted the rats' preference toward the cocaine-associated compartment. Altogether, these results suggest that social interaction reward engages CaMKII in the NAc.

Is It Possible to Shift from Down to Top Rank? A Focus on the Mesolimbic Dopaminergic System and Cocaine Abuse.

Impaired social behavior is a common feature of many psychiatric disorders, in particular with substance abuse disorders. Switching the preference of the substance-dependent individual toward social interaction activities remains one of the major challenges in drug dependence therapy. However, social interactions yield to the emergence of social ranking. In this review, we provide an overview of the studies that examined how social status can influence the dopaminergic mesolimbic system and how drug-seeking behavior is affected. Generally, social dominance is associated with an increase in dopamine D2/3 receptor binding in the striatum and a reduced behavioral response to drugs of abuse. However, it is not clear whether higher D2 receptor availability is a result of increased D2 receptor density and/or reduced dopamine release in the striatum. Here, we discuss the possibility of a potential shift from down to top rank via manipulation of the mesolimbic system. Identifying the neurobiology underlying a potential rank switch to a resilient phenotype is of particular interest in order to promote a positive coping behavior toward long-term abstinence from drugs of abuse and a protection against relapse to drugs. Such a shift may contribute to a more successful therapeutic approach to cocaine addiction.

Social interaction reward in rats has anti-stress effects.

Social interaction in an alternative context can be beneficial against drugs of abuse. Stress is known to be a risk factor that can exacerbate the effects of addictive drugs. In this study, we investigated whether the positive effects of social interaction are mediated through a decrease in stress levels. For that purpose, rats were trained to express cocaine or social interaction conditioned place preference (CPP). Behavioural, hormonal, and molecular stress markers were evaluated. We found that social CPP decreased the percentage of incorrect transitions of grooming and corticosterone to the level of naïve untreated rats. In addition, corticotropin-releasing factor (CRF) was increased in the bed nucleus of stria terminalis after cocaine CPP. In order to study the modulation of social CPP by the CRF system, rats received intracerebroventricular CRF or alpha-helical CRF, a nonselective antagonist of CRF receptors. The subsequent effects on CPP to cocaine or social interaction were observed. CRF injections increased cocaine CPP, whereas alpha-helical CRF injections decreased cocaine CPP. However, alpha-helical CRF injections potentiated social CPP. When social interaction was made available in an alternative context, CRF-induced increase of cocaine preference was reversed completely to the level of rats receiving cocaine paired with alpha-helical CRF. This reversal of cocaine preference was also paralleled by a reversal in CRF-induced increase of p38 MAPK expression in the nucleus accumbens shell. These findings suggest that social interaction could contribute as a valuable component in treatment of substance use disorders by reducing stress levels.

Is p38 MAPK Associated to Drugs of Abuse-Induced Abnormal Behaviors?

The family members of the mitogen-activated protein kinases (MAPK) mediate a wide variety of cellular behaviors in response to extracellular stimuli. p38 MAPKs are key signaling molecules in cellular responses to external stresses and regulation of pro-inflammatory cytokines. Some studies have suggested that p38 MAPK in the region of the nucleus accumbens is involved in abnormal behavioral responses induced by drugs of abuse. In this review, we discuss the role of the p38 MAPK in the rewarding effects of drugs of abuse. We also summarize the implication of p38 MAPK in stress, anxiety, and depression. We opine that p38 MAPK activation is more closely associated to stress-induced aversive responses rather than drug effects per se, in particular cocaine. p38 MAPK is only involved in cocaine reward, predominantly when promoted by stress. Downstream substrates of p38 that may contribute to the p38 MAPK associated-behavioral responses are proposed. Finally, we suggest p38 MAPK inhibitors as possible therapeutic interventions against stress-related disorders by potentially increasing resilience against stress and addiction relapse induced by adverse experiences.

Social interaction reward: A resilience approach to overcome vulnerability to drugs of abuse.

Drug addiction is a multifactorial disorder resulting from the complex interaction between biological, environmental and drug-induced effects. Generally, stress is a well-known risk factor for the development of drug addiction and relapse. While most of the research focuses on risk factors that increase the vulnerability to drugs of abuse, recent studies are focusing on the areas of strength/positive coping approaches that can increase resistance to drugs of abuse. In this review, we concentrate on resilience, seen as a dynamic process, which can allow individuals to positively adapt within the context of a specific risk for psychiatric illness. Here, we discuss the effects of social stress in animal models on drug use, particularly cocaine. In contrast, we suggest social interaction reward when available as an alternative to drug use as an approach contracting negative stress effects and increasing resistance to drug use. Indeed, interventions, which aim at enhancing resilience to stress through the facilitation of social interaction and the enhancement of social support, could be particularly effective in helping people cope with stress and preventing drug use problems or relapse. Finally, understanding the neurobiological mechanisms underlying protective factors such as social interaction reward should provide the basis for future evidence-based interventions targeting substance abuse and stress-related pathologies.

Involvement of cAMP-Dependent Protein Kinase in the Nucleus Accumbens in Cocaine Versus Social Interaction Reward.

Evidence suggests that PKA activity in the nucleus accumbens (NAc) plays an essential role in reward-related learning. In this study, we investigated whether PKA is differentially involved in the expression of learning produced by either natural reinforcers or psychostimulants. For that purpose, we inhibited PKA through a bilateral infusion of Rp-cAMPS, a specific PKA inhibitor, directly into the NAc. The effects of PKA inhibition in the NAc on the expression of concurrent conditioned place preference (CPP) for cocaine (drug) and social interaction (natural reward) in rats were evaluated. We found that PKA inhibition increased the expression of cocaine preference. This effect was not due to altered stress levels or decreased social reward. PKA inhibition did not affect the expression of natural reward as intra-NAc Rp-cAMPS infusion did not affect expression of social preference. When rats were trained to express cocaine or social interaction CPP and tested for eventual persisting preference 7 and 14 days after CPP expression, cocaine preference was persistent, but social preference was abolished after the first test. These results suggest that PKA in the NAc is involved in drug reward learning that might lead to addiction and that only drug, but not natural, reward is persistent.

Cocaine Paired Environment Increases SATB2 Levels in the Rat Paraventricular Thalamus.

SATB2 is a DNA binding protein that specifically binds the nuclear matrix attachment region and functions as a regulator of the transcription of large chromatin domains. Unlike its well addressed role during brain development, the role of SATB2 in adult brain is under-investigated. It has been shown that deletion of SATB2 from the forebrain of adult mice significantly impaired long-term memory for contextual fear and object recognition memory. The aim of the present study was to investigate the effects of appetitive stimuli such as cocaine and social interaction (SI) on SATB2 expression in the adult rat brain. For that, we performed conditioned place preference (CPP) to cocaine (15 mg/kg) and to SI, then assessed SATB2 expression in the brain 1 h (24 h after the last conditioning) and 24 h (48 h after the last conditioning) after the CPP test. We found that SATB2 expression in the paraventricular thalamus of rats was increased 1 h after the cocaine CPP test. This increase was selective for the cocaine-paired environment since the SI-paired environment did not increase SATB2 expression in the paraventricular thalamus. Also, the cocaine paired environment-induced increase of SATB2 levels in the paraventricular thalamus was due to cocaine conditioning as the unpaired cocaine group did not show an increase of SATB2 in the paraventricular thalamus. These results suggest that SATB2 in the paraventricular thalamus appears to be involved in the association between cocaine effects and environmental context. Further studies are needed to address the functional role of SATB2 in cocaine conditioning.

Preventive Strength of Dyadic Social Interaction against Reacquisition/Reexpression of Cocaine Conditioned Place Preference.

The reorientation away from drugs of abuse and toward social interaction is a highly desirable but as yet elusive goal in the therapy of substance dependence. We could previously show that cocaine preferring Sprague-Dawley rats which engaged in only four 15 min episodes of dyadic social interaction (DSI) did not reacquire and reexpress cocaine conditioned place preference (CPP) after a single cocaine exposure. In the present study, we investigated how strong this preventive effect of DSI is. In corroboration of our previous findings in rats, four 15 min DSI episodes prevented the reacquisition/reexpression of cocaine CPP in mice. However, this effect was only observed if only one cocaine conditioning session (15 min) was used. If mice were counterconditioned with a total of four cocaine sessions, the cocaine CPP reemerged. Interestingly, the opposite also held true: in mice that had acquired/expressed cocaine CPP, one conditioning session with DSI did not prevent the persistence of cocaine CPP, whereas four DSI conditioning sessions reversed CPP for 15 mg/kg intraperitoneal cocaine. Of note, this cocaine dose was a strong reward in C57BL/6J mice, causing CPP in all tested animals. Our findings suggest that both the reversal (reconditioning) of CPP from cocaine to DSI as well as that from DSI to cocaine requires four conditioning sessions. As previously shown in C57BL/6 mice from the NIH substrain, mice from the Jackson substrain also showed a greater relative preference for 15 mg/kg intraperitoneal cocaine over DSI, whereas Sprague-Dawley rats were equally attracted to contextual stimuli associated with this cocaine dose and DSI. Also in corroboration of previous findings, both C57BL/6J mice and experimenters several generations removed from the original ones produced CPP for DSI to a lesser degree than Sprague-Dawley rats. Our findings demonstrate the robustness of our experimental model across several subject- and experimenter generations in two rodent genus (i.e., mouse and rat) and allow the quantification of the strength (i.e., persistence) of the preventive effect of DSI against the reacquisition/reexpression of cocaine CPP, arguably a model for cocaine relapse.

The Two Faces of Social Interaction Reward in Animal Models of Drug Dependence.

Drug dependence is a serious health and social problem. Social factors can modify vulnerability to developing drug dependence, acting as risk factors or protective factors. Whereas stress and peer environment that encourage substance use may increase drug taking, strong attachments between family members and peer environment that do not experience drug use may protect against drug taking and, ultimately, drug dependence. The rewarding effects of drug abuse and social interaction can be evaluated using animal models. In this review we focus on evaluating social interaction reward in the conditioned place preference paradigm. We give an overview of how social interaction, if made available within the drug context, may facilitate, promote and interact with the drug's effects. However, social interaction, if offered alternatively outside the drug context, may have pronounced protective effects against drug abuse and relapse. We also address the importance of the weight difference parameter between the social partners in determining the positive or "agonistic" versus the hostile or "antagonistic" social interaction. We conclude that understanding social interaction reward and its subsequent effects on drug reward is sorely needed for therapeutic interventions against drug dependence.

Social interaction reward decreases p38 activation in the nucleus accumbens shell of rats.

We have previously shown that animals acquired robust conditioned place preference (CPP) to either social interaction alone or cocaine alone. Recently it has been reported that drugs of abuse abnormally activated p38, a member of mitogen-activated protein kinase family, in the nucleus accumbens. In this study, we aimed to investigate the expression of the activated form of p38 (pp38) in the nucleus accumbens shell and core of rats expressing either cocaine CPP or social interaction CPP 1 h, 2 h and 24 h after the CPP test. We hypothesized that cocaine CPP will increase pp38 in the nucleus accumbens shell/core as compared to social interaction CPP. Surprisingly, we found that 24 h after social interaction CPP, pp38 neuronal levels were decreased in the nucleus accumbens shell to the level of naïve rats. Control saline rats that received saline in both compartments of the CPP apparatus and cocaine CPP rats showed similar enhanced p38 activation as compared to naïve and social interaction CPP rats. We also found that the percentage of neurons expressing dopaminergic receptor D2R and pp38 was also decreased in the shell of the nucleus accumbens of social interaction CPP rats as compared to controls. Given the emerging role of p38 in stress/anxiety behaviors, these results suggest that (1) social interaction reward has anti-stress effects; (2) cocaine conditioning per se does not affect p38 activation and that (3) marginal stress is sufficient to induce p38 activation in the shell of the nucleus accumbens.

Social interaction and cocaine conditioning in mice increase spontaneous spike frequency in the nucleus accumbens or septal nuclei as revealed by multielectrode array recordings.

Both cocaine and social interaction place preference conditioning lead to increased neuronal expression of the immediate early gene EGR1 in the nucleus accumbens, a central region of the reward pathway, suggesting that both drug and natural rewards may be processed in similar brain regions. In order to gain novel insights into the intrinsic in vitro electrical activity of the nucleus accumbens and adjacent brain regions and to explore the effects of reward conditioning on network activity, we performed multielectrode array recordings of spontaneous firing in acute brain slices of mice conditioned to either cocaine or social interaction place preference. Cocaine conditioning increased the spike frequency of neurons in the septal nuclei, whereas social interaction conditioning increased the spike frequency in the nucleus accumbens compared to saline control animals. In addition, social interaction conditioning decreased the amount of active neuron clusters in the nucleus accumbens. Our findings suggest that place preference conditioning for both drug and natural rewards may induce persistent changes in neuronal network activity in the nucleus accumbens and the septum that are still preserved in acute slice preparations.

Differences in social interaction- vs. cocaine reward in mouse vs. rat.

We previously developed rat experimental models based on the conditioned place preference (CPP) paradigm in which only four 15-min episodes of dyadic social interaction with a sex- and weight-matched male Sprague Dawley (SD) rat (1) reversed CPP from cocaine to social interaction despite continuing cocaine training, and (2) prevented the reacquisition/re-expression of cocaine CPP. In a concurrent conditioning schedule, pairing one compartment with social interaction and the other compartment with 15 mg/kg cocaine injections, rats spent the same amount of time in both compartments and the most rewarding sensory component of the composite stimulus social interaction was touch (taction). In the present study, we validated our experimental paradigm in C57BL/6 mice to investigate if our experimental paradigm may be useful for the considerable number of genetically modified mouse models. Only 71% of the tested mice developed place preference for social interaction, whereas 85% of the rats did. Accordingly, 29% of the mice developed conditioned place aversion (CPA) to social interaction, whereas this was true for only 15% of the rats. In support of the lesser likelihood of mice to develop a preference for social interaction, the average amount of time spent in direct contact was 17% for mice vs. 79% for rats. In animals that were concurrently conditioned for social interaction vs. cocaine, the relative reward strength for cocaine was 300-fold higher in mice than in rats. Considering that human addicts regularly prefer drugs of abuse to drug-free social interaction, the present findings suggest that our experimental paradigm of concurrent CPP for cocaine vs. social interaction is of even greater translational power if performed in C57BL/6 mice, the genetic background for most transgenic rodent models, than in rats.

Brain regions associated with the acquisition of conditioned place preference for cocaine vs. social interaction.

Positive social interaction could play an essential role in switching the preference of the substance dependent individual away from drug related activities. We have previously shown that conditioned place preference (CPP) for cocaine at the dose of 15 mg/kg and CPP for four 15-min episodes of social interaction were equally strong when rats were concurrently conditioned for place preference by pairing cocaine with one compartment and social interaction with the other. The aim of the present study was to investigate the differential activation of brain regions related to the reward circuitry after acquisition/expression of cocaine CPP or social interaction CPP. Our findings indicate that cocaine CPP and social interaction CPP activated almost the same brain regions. However, the granular insular cortex and the dorsal part of the agranular insular cortex were more activated after cocaine CPP, whereas the prelimbic cortex and the core subregion of the nucleus accumbens were more activated after social interaction CPP. These results suggest that the insular cortex appears to be potently activated after drug conditioning learning while activation of the prelimbic cortex-nucleus accumbens core projection seems to be preferentially involved in the conditioning to non-drug stimuli such as social interaction.