Abstract
Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is often observed in alcoholics and humans subjected to early life stress, and animal models of ethanol (EtOH) dependence. We examined HPA axis function in a rodent model of early life stress that engenders increases in behavioral and neurobiological risk factors of alcoholism. Long-Evans male rats were group housed (GH) or socially isolated (SI) for 6 weeks during adolescence. We examined the corticosterone (CORT) response to stress with and without dexamethasone (DEX) and anxiety-like behaviors. Following the DEX suppression test and behavioral assays, half of the cohort engaged in 6 weeks of EtOH drinking in a homecage, two-bottle choice intermittent access model. A subset of the cohort was not exposed to EtOH, but was used for electrophysiological measurement of glutamatergic synaptic plasticity in the basolateral amygdala (BLA). Correlational analyses examined relationships between measures of CORT, anxiety-like behaviors, and EtOH intake/preference. With DEX pre-treatment, SI rats failed to suppress CORT in response to an acute stress; GH rats showed a significant suppression. In SI rats, there was a significant negative correlation between baseline CORT and elevated plus maze open arm time, as well as significant positive correlations between baseline CORT and both EtOH intake and preference. No significant relationships between baseline CORT and behavioral measures were observed in GH rats. Glutamatergic plasticity in the BLA was similar in magnitude between GH and SI rats, and was not altered by exogenous application of CORT. These data suggest that HPA axis function is affected by SI, and this is related to antecedent anxiety-like behavior and may predispose for future EtOH self-administration. Relationships between HPA axis function, anxiety, and EtOH measures in SI rats further strengthens the utility of this paradigm in modeling vulnerability for affective disorders and alcoholism.
Highlights
Life stress is correlated with both hypothalamic–pituitary– adrenal (HPA) axis dysfunction and alcoholism in humans (Lovallo, 2012)
There was a statistically significant interaction for time spent in the center of the open field, [F(11,407) = 1.951, p < 0.05], though post hoc tests indicated that this effect was driven by time, as no difference between groups was detected at any individual time point
DEXAMETHASONE SUPPRESSION TEST Given the within-subject design, counterbalanced 2-day testing procedure used for the DEX suppression test (DST), baseline CORT levels were averaged for the two testing days for comparison of baseline CORT values between groups
Summary
Life stress is correlated with both hypothalamic–pituitary– adrenal (HPA) axis dysfunction and alcoholism in humans (Lovallo, 2012). HPA axis dysfunction may include reduced or increased responsiveness to stressors as measured by circulating levels of corticosterone (CORT) and impaired dexamethasone (DEX) suppression of CORT, both of which have been noted in dependent individuals and individuals at-risk for ethanol (EtOH) dependence. Whether HPA axis dysfunction precedes or is a consequence of EtOH dependence, pharmacological reduction of stress, anxiety, and negative affect reduces EtOH craving in alcohol dependent individuals, suggesting that normalizing function of the HPA axis and/or reducing stress/anxiety may be efficacious treatment targets for EtOH dependence/relapse (Breese et al, 2011; Fox et al, 2011). Besemer et al (2011) reported that failure to suppress cortisol levels on the DEX suppression test (DST) and increased urinary cortisol are among the most consistent measures of HPA axis dysfunction reported in alcohol-induced Cushing syndrome
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