Abstract
Forced abstinence (FA) from alcohol has been shown to produce a variety of anxiety- and depression-like symptoms in animal models. Somatostatin (SST) neurons, a subtype of GABAergic neurons found throughout the brain, are a novel neural target with potential treatment implications in affective disorders, yet their role in alcohol use disorders (AUD) remains to be explored. Here, we examined the neuroadaptations of SST neurons during forced abstinence from voluntary alcohol consumption. Following 6 weeks of two-bottle choice alcohol consumption and protracted forced abstinence, male and female C57BL/6J mice exhibited a heightened, but sex-specific, depressive-like behavioral profile in the sucrose preference test (SPT) and forced swim test (FST), without changes in anxiety-like behaviors in the elevated plus maze (EPM) and open field test (OFT). FST-induced cFos expressions in the prefrontal cortex (PFC) and ventral bed nucleus of the stria terminalis (vBNST) were altered in FA-exposed female mice only, suggesting a sex-specific effect of forced abstinence on the neural response to acute stress. SST immunoreactivity in these regions was unaffected by forced abstinence, while differences were seen in SST/cFos co-expression in the vBNST. No differences in cFos or SST immunoreactivity were seen in the lateral central nucleus of the amygdala (CEA) and the basolateral amygdala (BLA). Additionally, SST neurons in female mice displayed opposing alterations in the PFC and vBNST, with heightened intrinsic excitability in the PFC and diminished intrinsic excitability in the vBNST. These findings provide an overall framework of forced abstinence-induced neuroadaptations in these key brain regions involved in emotional regulation and processing.
Highlights
Alcohol use disorder (AUD) represents one of the most prevalent and costly neuropsychiatric disorders globally and domestically, costing the United States economy an estimated $249 billion due to losses in workplace productivity, and health care and criminal justice expenses (Sacks et al, 2015)
Alcohol preference over water did not differ between male and female mice [Ftime(5, 95) = 5.839, p < 0.001, Fsex(1, 19) = 0.041, p = 0.84, Fsex × time(5, 95) = 0.535, p = 0.749], and both sexes displayed a strong preference for alcohol over water [male: one-sample t(10) = 5.391, p < 0.001, female: one-sample t(9) = 7.102, p < 0.001] (Figure 1C)
In the elevated plus maze (EPM), open arm duration was comparable between sexes and alcohol conditions [Fsex(1, 39) = 0.379, p = 0.531, FFA(1, 39) = 0.991, p = 0.325, Fsex × Forced abstinence (FA)(1, 39) = 0.4, p = 0.530; Figure 2A]
Summary
Alcohol use disorder (AUD) represents one of the most prevalent and costly neuropsychiatric disorders globally and domestically, costing the United States economy an estimated $249 billion due to losses in workplace productivity, and health care and criminal justice expenses (Sacks et al, 2015). Withdrawal from alcohol (both acute and protracted withdrawal) produces a host of negative emotional conditions, such as depression and anxiety (Hershon, 1977; Becker, 2014; Smith et al, 2019). These emotional states can increase the risk for relapse and further hamper an individual’s ability to abstain from alcohol. Complementary research suggests that alleviating depressive symptoms following abstinence from alcohol may improve treatment outcomes for women (Annis et al, 1998; Holzhauer and Gamble, 2017) Taken together, these data point to a complex relationship between AUD, depression, and treatment outcome, likely moderated by sex
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