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

Abstract

Neuroactive steroids such as (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone) are potent neuromodulators that enhance GABAergic neurotransmission and produce inhibitory neurobehavioral and anti-inflammatory effects. Chronic ethanol (EtOH) consumption reduces 3α,5α-THP levels in human plasma, but has brain region- and species-specific effects on central nervous system levels of 3α,5α-THP. We explored the relationship between 3α,5α-THP levels in the hippocampus and voluntary EtOH consumption in the cynomolgus monkey following daily self-administration of EtOH for 12months 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. Monkeys were subjected to scheduled induction of water and EtOH consumption (0 to 1.5g/kg) over 4months, followed by free access to EtOH or water for 22h/d over 12 months. Immunohistochemistry was performed using an anti-3α,5α-THP or anti-MCP-1 antibody. Prolonged voluntary drinking resulted in individual differences in EtOH consumption that ranged from 1.2 to 4.2g/kg/d over 12months. Prolonged EtOH consumption increased cellular 3α,5α-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 ≥3g/kg for ≥20% of days. 3α,5α-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, 3α,5α-THP and MCP-1 immunoreactivity were inversely correlated with each other (Spearman r=-0.68, p<0.05). These data indicate that voluntary, long-term EtOH consumption results in higher levels of 3α,5α-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.