Neuroactive Steroid (3alpha,5alpha)3-hydroxypregnan-20-one (3alpha,5alpha-THP) and Pro-inflammatory Cytokine MCP-1 Levels in Hippocampus CA1 are Correlated with Voluntary Ethanol Consumption in Cynomolgus Monkey

Background: Neuroactive steroids such as (3a,5a)3-hydroxypregnan-20-one (3a,5a-THP, allopregnanolone) are potent neuromodulators that enhance GABAergic neurotransmission and produce inhibitory neurobehavioral and anti-inflammatory effects. Chronic ethanol (EtOH) consumption reduces 3a,5a-THP levels in human plasma, but has brain region- and species-specific effects on central nervous system levels of 3a,5a-THP. We explored the relationship between 3a,5a-THP levels in the hippocampus and voluntary EtOH consumption in the cynomolgus monkey following daily self-administration of EtOH for 12 months and further examined the relationship with hypothalamic-pituitary-adrenal (HPA) axis function prior to EtOH exposure. We simultaneously explored hippocampus levels of monocyte chemoattractant protein 1 (MCP-1), a pro-inflammatory cytokine that plays an important role in the neuroimmune response to EtOH, following chronic self-administration. Methods: Monkeys were subjected to scheduled induction of water and EtOH consumption (0 to 1.5 g/kg) over 4 months, followed by free access to EtOH or water for 22 h/d over 12 months. Immunohistochemistry was performed using an anti-3a,5a-THP or anti-MCP-1 antibody. Prolonged voluntary drinking resulted in individual differences in EtOH consumption that ranged from 1.2 to 4.2 g/kg/d over 12 months. Results: Prolonged EtOH consumption increased cellular 3a,5a-THP immunoreactivity by 12 ± 2% (p < 0.05) and reduced MCP-1 immunoreactivity by 23 ± 9% (p < 0.05) in the hippocampus CA1. In both cases, the effect of EtOH was most pronounced in heavy drinkers that consumed >=3 g/kg for >=20% of days. 3a,5a-THP immunoreactivity was positively correlated with average daily EtOH intake (Spearman r = 0.76, p < 0.05) and dexamethasone inhibition of HPA axis function (Spearman r = 0.9, p < 0.05). In contrast, MCP-1 immunoreactivity was negatively correlated with average daily EtOH intake (Spearman r = -0.78, p < 0.05) and dexamethasone suppression of HPA axis function (Spearman r = -0.76, p < 0.05). Finally, 3a,5a-THP and MCP-1 immunoreactivity were inversely correlated with each other (Spearman r = -0.68, p < 0.05). Conclusions: These data indicate that voluntary, long-term EtOH consumption results in higher levels of 3a,5a-THP, while decreasing levels of MCP-1 in the CA1 hippocampus, and that both changes may be linked to HPA axis function and the magnitude of voluntary EtOH consumption.