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Neuroactive Steroid (3 α ,5 α )3‐hydroxypregnan‐20‐one (3 α ,5 α ‐ THP ) and Pro‐inflammatory Cytokine MCP ‐1 Levels in Hippocampus CA 1 are Correlated with Voluntary Ethanol Consumption in Cynomolgus Monkey
Author(s) -
Beattie Matthew C.,
Reguyal Christopher S.,
Porcu Patrizia,
Daunais James B.,
Grant Kathleen A.,
Morrow A. Leslie
Publication year - 2018
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13545
Subject(s) - allopregnanolone , neuroactive steroid , hippocampus , endocrinology , medicine , pregnanolone , monocyte , chemistry , hypothalamus , cytokine , thp1 cell line , pharmacology , gabaa receptor , receptor , biology , cell culture , genetics
Background Neuroactive steroids such as (3 α ,5 α )3‐hydroxypregnan‐20‐one (3 α ,5 α ‐ THP , allopregnanolone) are potent neuromodulators that enhance GABA ergic neurotransmission and produce inhibitory neurobehavioral and anti‐inflammatory effects. Chronic ethanol (EtOH) consumption reduces 3 α ,5 α ‐ THP levels in human plasma, but has brain region‐ and species‐specific effects on central nervous system levels of 3 α ,5 α ‐ THP . We explored the relationship between 3 α ,5 α ‐ 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‐3 α ,5 α ‐ 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 3 α ,5 α ‐ THP immunoreactivity by 12 ± 2% ( p < 0.05) and reduced MCP ‐1 immunoreactivity by 23 ± 9% ( p < 0.05) in the hippocampus CA 1. In both cases, the effect of EtOH was most pronounced in heavy drinkers that consumed ≥3 g/kg for ≥20% of days. 3 α ,5 α ‐ 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, 3 α ,5 α ‐ 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 3 α ,5 α ‐ THP , while decreasing levels of MCP ‐1 in the CA 1 hippocampus, and that both changes may be linked to HPA axis function and the magnitude of voluntary EtOH consumption.