Cytokine MCP-1 Levels in Hippocampus CA1 are Correlated with Voluntary Ethanol Consumption in Cynomolgus Monkey


Matthew C. Beattie, Christopher S. Reguyal, Patrizia Porcu, James B. Daunais, Kathleen A. Grant, A. Leslie Morrow


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 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.

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-3α,5α-THP or anti-MCP-1 antibody. Prolonged voluntary drinking resulted in individual differences in EtOH consumption that ranged from 1.2 to 4.2 g/kg/d over 12 months.

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 ≥3 g/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.