Changes In Glucocorticoid Receptor Sensitivity Following Long-Term Ethanol Self-Administration In Male And Female Rhesus Macaques

Stress can alter ethanol consumption and long-term use results in adaptation of the stress response, highlighting a bidirectional relationship that remains poorly understood. Non-human primates are an excellent model to investigate the interaction of stress and long-term ethanol use due to their similar neuroendocrine system to humans and propensity to chronically drink intoxicating amounts of alcohol. Here, circulating stress hormones (adrenocorticotropin hormone (ACTH) and cortisol) were measured in response to a low (17 mg/kg) and high (130 mg/kg) dose of dexamethasone, a potent glucocorticoid receptor (GR) agonist. The dexamethasone response was compared before (baseline) and after 7 months of daily 22 h/d ethanol self-administration in young adult male (n=6) and female (n=6) rhesus macaques. At both timepoints, the high dose dexamethasone challenge resulted in 90-100% suppression of both ACTH and cortisol with no difference between sexes. At baseline, low dose dexamethasone reduced both ACTH and cortisol, but to a lesser degree and with greater between-subject variability, 0 – 60%. Following seven-months of daily ethanol consumption (average intakes ranging from 0.6 – 4.0 g/kg/day) the response to low dose dexamethasone was greater. This effect was more robust in females compared to males. Additionally, the change in suppression between baseline and following long-term daily ethanol consumption correlated with daily intake, such that the magnitude of change over time was greater in heavier drinkers. Because stress increases reliance on putamen-dependent or habitual behavior and heavy ethanol drinking leads to excitatory-inhibitory neurotransmission imbalance within the putamen, we tested the hypothesis that long-term ethanol self-administration will alter striatal transmission via the GR. Therefore, we used whole cell patch clamp electrophysiology to investigate the effect of bath application of dexamethasone onto putamen medium spiny neurons (MSNs). Dexamethasone rapidly decreased the area and amplitude of spontaneous inhibitory postsynaptic currents among binge drinkers. These data show that acute dexamethasone, presumably via activation of the membrane bound GR, activated fewer GABAergic receptors among binge drinkers. These data highlight a unique role of the GR within the putamen that may mediate stress dependent changes contributing to addiction vulnerability, particularly among binge drinkers.