Adolescent social isolation increases cocaine seeking in male and female mice

Abstract

Childhood and adolescent adversity are associated with a wide range of psychiatric disorders, including an increased risk for substance abuse. Despite this, the mechanisms underlying the ability of chronic stress during adolescence to alter reward signaling remains largely unexplored. Understanding how adolescent stress increases addiction-like phenotypes could inform the development of targeted interventions both before and after drug use. The current study examined how prolonged isolation stress, beginning during adolescence, affected behavioral and neuronal underpinnings to the response to cocaine in male and female mice. Adolescent-onset social isolation did not alter the ability of mice to learn an operant response for food, nor influence food self-administration or motivation for food on a progressive ratio schedule. However, male and female social isolation mice exhibited an increase in motivation for cocaine and cocaine seeking during a cue-induced reinstatement session. Additionally, we demonstrated that adolescent-onset social isolation increased cocaine-induced neuronal activation, as assessed by c-Fos expression, within the nucleus accumbens core and shell, ventral pallidum, dorsal bed nucleus of the stria terminalis, lateral septum and basolateral amygdala. Taken together, the present studies demonstrate that social isolation stress during adolescence augments the behavioral responses to cocaine during adulthood and alters the responsiveness of reward-related brain circuitry.

Social isolation enhances cued-reinstatement of sucrose and nicotine seeking, but this is reversed by a return to social housing

“…Notably, there were no differences in responding in reward-primed reinstatement, suggesting that the reward itself was equally valued across housing conditions. This pattern of results is largely consistent with previous literature, where both social isolation or an impoverished physical environment have been shown to enhance cue-induced reinstatement of cocaine seeking, with little impact on drug reinstatement 34 , 35 , 47 . It suggests that social isolation enhances the encoding of reward-related cues across acquisition of both nicotine and sucrose self-administration, and that following extinction, these cues are more readily able to reinstate reward seeking.…”

“…Socially isolated rats also show an altered response to drugs of abuse, including facilitated acquisition of nicotine, cocaine and heroin 30 – 32 self-administration, which has been linked to interactions with the hypothalamic–pituitary–adrenal (HPA) axis 33 . However, social isolation may also change sensitivity towards and in response to drug-paired cues, with evidence of enhanced reinstatement to methamphetamine-paired cues in mice 34 and cocaine-paired cues in rats 35 . Together these studies suggest that social isolation alters the way rats react to cues in their environment that either predict or are associated with both highly palatable food and drug rewards.…”

Reward Circuitry and Motivational Deficits in Social Anxiety Disorder: What Can Be Learned From Mouse Models?

“…The DA system is significantly impacted by this paradigm, such that following social isolation, mice have demonstrated increased DA-receptor 2 mRNA and protein levels in the NAc, suggestive of excessive dopaminergic activity in mesolimbic areas that are key to motivation and reward salience (Li et al, 2017). Additionally, following social isolation in adolescence, mice show increases in mesolimbic DA-ergic activation in response to cocaine in adulthood, thereby suggesting a long-term impact of social stress on reward sensitivity that persists throughout development (Fosnocht et al, 2019).…”

“…Whereas results from the other animal paradigms reviewed here (SDS and social instability) seem to more directly parallel observations in humans of elevated social anxiety symptoms in chaotic/abusive home environments and/or bullying, social isolation during adolescence may be a relevant model for characterizing social deficits that develop in the context of early adversity during adolescence and are perpetuated by disorderrelated social avoidance. Given that experimental evidence in mice (e.g., Fosnocht et al, 2019) illustrates that isolation during adolescence can result in altered reward responsiveness, suggesting that teens who are socially isolated, even in the absence of other social stressors, may experience long-lasting anhedonic symptoms mediated by altering the responsiveness of reward-related brain circuitry. Again, this should be considered with caution, as these animal models can only provide clues toward these potential risk-factors that induce altered reward responsiveness given that a mouse model will never fully capture the complexity of the environmental and social phenomena within the human experience.…”

Psychisch krank in Krisenzeiten: Subjektive Belastungen durch COVID-19

“…In den Freitextantworten wurde sehr häufig der fehlende Kontakt zu den Angehörigen als besonders belastend genannt. Grundsätzlich wurde soziale Isolation als Risikofaktor für die Entwicklung psychischer Störungen identifiziert [25,26].…”