ABSTRACT
Chronic stress during adolescence increases the susceptibility to many neuropsychiatric diseases in adulthood, including anxiety-like and alcohol drinking behaviors. Social isolation is a particularly profound stressor with increasing human relevance, especially during the COVID-19 pandemic, when millions of adolescents faced prolonged periods of isolation. However, preclinical rodent models of adolescent social stress have produced mixed results that are often sex, species and strain-dependent. Here we examined the effect of intermittent social isolation on alcohol intake and preference during adolescence (PND28-56) and its long-term effects and alcohol drinking on anxiety, irritability, and synaptic transmission in both male and female Wistar rats. To this goal, we developed and utilized a new model of social isolation and alcohol exposure whereby adolescent (PND28) male and female rats were intermittently socially isolated for 24h prior to 2-bottle choice (2BC) access to ethanol (20% v/v, 2h/session, Tues/Thur/Sat) vs. water, for 4 weeks. Two weeks later (young adults), all rats were tested for anxiety in the novelty induced hypophagia test and irritability-like behavior in the bottle brush test, and a subset was used to record spontaneous inhibitory GABAergic postsynaptic currents (sIPSCs) in the central nucleus of the amygdala (CeA). Additionally, we studied genetically selected Marchigian Sardinian alcohol-preferring (msP) rats to compare the effects of social isolation in a rat strain of increased alcohol preference vulnerability and high sensitivity to anxiety. Social isolation increased alcohol preference in both male and female Wistars when compared to the group-housed controls, starting from week 1 and throughout adolescence. All msP rats displayed escalation of drinking during week 1 and 2 and the effect of the isolation was observed starting from week 3 in males only. No isolation effects were observed in female msPs throughout the 4 weeks. Social isolation and alcohol drinking during adolescence increased aggressive-like behavior in male adult Wistar rats, but not females, and did not alter anxiety measures. Baseline frequency of sIPSCs was decreased in socially isolated male Wistar and msP adult rats vs. group-housed, while rise times, amplitudes, and decay times remained unchanged, indicating reduced basal presynaptic GABA release in the CeA. Together, these findings suggest that an intermittent social isolation produces increased alcohol preference in Wistar rats of both sexes and in male msPs, as well as synaptic changes in the CeA.Copyright © 2023
ABSTRACT
Chronic stress during the developmental period of adolescence increases the susceptibility to many neuropsychiatric diseases in adulthood, including anxiety-like and alcohol drinking behaviors. Social isolation is a particularly profound stressor with increasing human relevance, especially during the COVID-19 pandemic, when millions of adolescents have faced prolonged periods of isolation. Preclinical rodent models of adolescent isolation stress have produced mixed results that are often sex, species, and strain dependent. Here, we examined the effect of intermittent social isolation on alcohol intake and preference during adolescence (PND 28-56) in male and female Wistar rats and the long-term effects of juvenile social isolation and alcohol drinking on anxiety-and irritability-like behaviors. Furthermore, we studied genetically selected Marchigian Sardinian alcohol-preferring (msP) rats to compare the effects of social isolation in a rat strain of increased innate alcohol preference and high sensitivity to stress and anxiety. We developed and utilized a new model of social isolation and alcohol exposure whereby male and female rats beginning at PND28 were intermittently socially isolated for 24h prior to 2-bottle choice (2BC) access to ethanol (20%v/v, 2h/session) vs. water. After each session, the rats were regrouped until the next day when they were isolated again. This procedure was repeated for 3 days/week across 4 weeks. Two weeks later, as young adults (PND 80), all rats were tested for anxiety in the novelty induced hypophagia test and irritability in the bottle brush test. Social isolation increased alcohol preference in both male and female Wistars when compared to the group-housed control group, starting from week 1 and throughout adolescence. All msP rats displayed escalation of drinking during week 1 and 2 and the effect of the isolation was observed starting from week 3 in males only. No isolation effects were observed in female msPs throughout the 4 weeks. Social isolation and alcohol drinking during adolescence increased aggressive-like behavior in male adult Wistar rats, but not females, and did not alter anxiety measures. Together, these findings suggest that an intermittent social isolation followed by re-grouping produces increased alcohol preference in Wistar rats of both sexes and, with a different trend, in male msPs. Ongoing studies are elucidating the underlying physiological mechanisms.