Vicarious Social Defeat Increases Conditioned Rewarding Effects of Cocaine and Ethanol Intake in Female Mice.

Stress is a critical factor in the development of mood and drug use disorders. The social defeat model is not appropriate for female rodents due to their low level of aggression. Therefore, a robust female model of social stress needs to be developed and validated. The aim of the present study was to unravel the long-lasting effects of vicarious social defeat (VSD) on the conditioned rewarding effects of cocaine and ethanol intake in female mice. Although VSD seems to be a good model for inducing behavioral and physiologic endophenotypes induced by stress, there are no studies to date that characterize the effect of VSD on cocaine or alcohol use. The results confirm that VSD females showed an increase in corticosterone levels after a vicarious experience while also displaying an increase in anxiety- and anhedonic-like behaviors. Three weeks after the last VSD, vicariously defeated female mice showed an increased developed preference for a non-effective dose of cocaine in the conditioned place preference (CPP) paradigm and showed an increase in ethanol intake. Our results suggest that female mice vicariously experience a state of distress through the social observation of others suffering from adverse events, confirming the use of VSD as a valid model to study the response to social stress in females. The fact that VSD in females induced a comparable behavioral phenotype to that observed in physically defeated males could indicate a relationship with the higher rate of psychopathologies observed in women. Notwithstanding, more studies are needed to dissect the neurobiological and behavioral peculiarities of the female response to social stress.

Hormonal Profile in Response to an Empathic Induction Task in Perpetrators of Intimate Partner Violence: Oxytocin/Testosterone Ratio and Social Cognition.

Empathy deficits have been proposed to be an important factor for intimate partner violence (IPV). IPV perpetrators have shown a differential change in salivary oxytocin (sOXT), testosterone (sT), and cortisol (sC), following empathic and stress tasks, compared to non-violent men. However, the influence of empathic deficits in those hormones after an emotion-induction task in IPV perpetrators remains unclear. We analyzed the effects of an empathic induction task on endogenous sOXT, sT and sC levels, as well as their hormonal ratios, in IPV perpetrators (n = 12), and compared them to controls (n = 12). Additionally, we explored the predictive capacity of empathy-related functions (measured with the interpersonal reactivity index) in the hormonal responses to the task. IPV perpetrators presented lower sOXT changes and higher total sT levels than controls after the task, lower sOXT/T change and total sOXT/T levels, as well as higher total sT/C levels. Notably, for all participants, the lower the perspective taking score, the lower the total sOXT levels and sOXT changes and the higher the sT changes were. Low perspective taking also predicted smaller sOXT/T and sOXT/C changes in the empathic induction task, and higher total sT/C levels for all participants. Therefore, our results could contribute to furthering our ability to focus on new therapeutic targets, increasing the effectiveness of intervention programs and helping to reduce IPV recidivism in the medium term.

Prepulse inhibition can predict the motivational effects of cocaine in female mice exposed to maternal separation.

The prepulse inhibition (PPI) of the startle response can identify the rodents that are more sensitive to the effects of cocaine. Mice with a lower PPI presented a higher vulnerability to the effects of cocaine and a higher susceptibility to developing a substance use disorder (SUD). Maternal separation with early weaning (MSEW) is a relevant animal model to induce motivational alterations throughout life. Nevertheless, only a few studies on females exist, even though they are more vulnerable to stress- and cocaine-related problems. Hence, the aim of the present study was to evaluate the ability of PPI to identify females with a greater vulnerability to the long-term consequences of early stress on the motivational effects of cocaine. Female mice underwent MSEW and were classified according to their high or low PPI. They were then assessed in the cocaine-induced locomotor sensitization test, the conditioned place preference paradigm or the operant self-administration paradigm. Additionally, they were also evaluated in the passive avoidance task, the tail-suspension and the splash tests. The results revealed that the females with lower PPI presented higher consequences of MSEW on the effects of cocaine and showed an increase in anhedonia-like behaviours. Our findings support that a PPI deficit could represent a biomarker of vulnerability to the effects of cocaine induced by MSEW.

Impact of adolescent methamphetamine use on social cognition: A human-mice reverse translation study.

BACKGROUND: Methamphetamine dependence is associated with social cognition deficits that may underpin negative social outcomes. However, there are considerable inter-individual differences in social cognition within people with methamphetamine dependence, with age of onset of methamphetamine use being a potential contributing factor. MATERIALS AND METHODS: We conducted two sequential studies examining the link between age of onset of methamphetamine use (adolescence versus young adulthood) and performance in social cognition tests: (1) a human cross-sectional study in 95 participants with methamphetamine dependence varying in age of onset (38 with adolescent onset and 57 with adult onset) and 49 drug-naïve controls; (2) a mice study in which we tested the effects of methamphetamine exposure during adolescence versus young adulthood on social interaction and aggression, and their potential neurochemical substrates in the striatal dopaminergic system. RESULTS: We initially showed that people with methamphetamine dependence who started use in adolescence had higher antisocial beliefs (p = 0.046, Cohen's d=0.42) and worse emotion recognition (p = 0.031, Cohen's d=0.44) than those who started use during adulthood. We reasoned that this could be due to either social cognition deficits leading to earlier onset of methamphetamine use, or methamphetamine-induced neuroadaptive effects specific to adolescence. Mice experiments showed that methamphetamine exposure during adolescence specifically decreased social investigation during social interaction and upregulated striatal tyrosine hydroxylase (p < 0.05, Bonferroni corrected). There was no evidence of adolescent-specific methamphetamine effects on aggression or other measures of dopaminergic function. CONCLUSION: Together, translational findings demonstrate heightened sensitivity to methamphetamine effects on social cognition during adolescence.

Prepulse Inhibition of the Startle Reflex as a Predictor of Vulnerability to Develop Locomotor Sensitization to Cocaine.

Prepulse inhibition (PPI) of the startle reflex is a measure of sensory-motor synchronization. A deficit in PPI has been observed in psychiatric patients, especially those with schizophrenia and vulnerable subjects, since the neural bases of this disorder are also involved in the regulation of PPI. Recently, we have reported that baseline PPI levels in mice can predict their sensitivity to the conditioned reinforcing effects of cocaine in the conditioned place preference (CPP) paradigm. Mice with a low PPI presented a lower sensitivity to the conditioned rewarding effects of cocaine; however, once they acquired conditioned preference with a higher dose of the drug, a more persistent associative effect of cocaine with respect to environmental cues was evident in these animals when compared with High-PPI mice. Therefore, we proposed that the PPI paradigm can determine subjects with a higher vulnerability to the effects of cocaine. Developing locomotor sensitization after pre-exposure to cocaine is considered an indicator of transitioning from recreational use to a compulsive consumption of the drug. Thus, the aim of the present study was to evaluate whether subjects with a low PPI display a higher locomotor sensitization induced by cocaine. First, male and female OF1 mice were classified as High- or Low-PPI according to their baseline PPI levels. Subsequently, the motor effects induced by an acute dose of cocaine (Experiments 1 and 2) and the development of locomotor sensitization induced by pre-exposure to this drug (Experiments 3 and 4) were recorded using two apparatuses (Ethovision and actimeter). Low-PPI mice presented low sensitivity to the motor effects of an acute dose of cocaine, but a high increase of activity after repeated administration of the drug, thus suggesting a great developed behavioral sensitization. Differences after pretreatment with cocaine vs. saline were more pronounced among Low-PPI subjects than among High-PPI animals. These results endorse our hypothesis that the PPI paradigm can detect subjects who are more likely to display behaviors induced by cocaine and which can increase the risk of developing a cocaine use disorder. Herein, we further discuss whether a PPI deficit can be considered an endophenotype for cocaine use disorder.

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse.

Social interaction is known to be the main source of stress in human beings, which explains the translational importance of this research in animals. Evidence reported over the last decade has revealed that, when exposed to social defeat experiences (brief episodes of social confrontations during adolescence and adulthood), the rodent brain undergoes remodeling and functional modifications, which in turn lead to an increase in the rewarding and reinstating effects of different drugs of abuse. The mechanisms by which social stress cause changes in the brain and behavior are unknown, and so the objective of this review is to contemplate how social defeat stress induces long-lasting consequences that modify the reward system. First of all, we will describe the most characteristic results of the short- and long-term consequences of social defeat stress on the rewarding effects of drugs of abuse such as psychostimulants and alcohol. Secondly, and throughout the review, we will carefully assess the neurobiological mechanisms underlying these effects, including changes in the dopaminergic system, corticotrophin releasing factor signaling, epigenetic modifications and the neuroinflammatory response. To conclude, we will consider the advantages and disadvantages and the translational value of the social defeat stress model, and will discuss challenges and future directions.

Social defeat in adolescent mice increases vulnerability to alcohol consumption.

This study employs an oral operant conditioning paradigm to evaluate the effects of repeated social defeat during adolescence on the reinforcing and motivational actions of ethanol in adult OF1 mice. Social interaction, emotional and cognitive behavioral aspects were also analyzed, and real-time polymerase chain reaction (PCR) experiments were performed to study gene expression changes in the mesocorticolimbic and hypothalamus-hypophysis-adrenal (HHA) axis. Social defeat did not alter anxiety-like behavior in the elevated plus maze or cognitive performance in the passive avoidance and Hebb-Williams tests. A social interaction test revealed depression-like symptoms and social subordination behavior in defeated OF1 mice. Interestingly, social defeat in adolescence significantly increased the number of effective responses, ethanol consumption values and motivation to drink. Finally, real-time PCR analyses revealed that social defeat significantly increased tyrosine hydroxylase and corticotropin-releasing hormone in the ventral tegmental area and paraventricular nucleus, respectively. In contrast, mu-opioid receptor gene expression was decreased in the nucleus accumbens of socially defeated mice. In summary, these findings suggest that exposure to social defeat during adolescence increases vulnerability to the rewarding effects of ethanol without affecting emotional or cognitive performance. The gene expression alterations we have observed in the mesocorticolimbic and HHA axis systems of defeated mice could be related with their increased ethanol consumption. These results endorse future research into pharmacological strategies that modulate these systems for the treatment of social stress-related alcohol consumption problems.