title: Voluntary ethanol consumption reduces GABAergic neuroactive steroid (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP) in the amygdala of the cynomolgus monkey.
abstract: Neuroactive steroids such as (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone) enhance the gamma-aminobutyric acid (GABA)-ergic effects of ethanol and modulate excessive drinking in rodents. Moreover, chronic ethanol consumption reduces 3α,5α-THP levels in human plasma, rat hippocampus and mouse limbic regions. We explored the relationship between 3α,5α-THP levels in limbic brain areas and voluntary ethanol consumption in the cynomolgus monkey following daily self-administration of ethanol for 12 months and further examined the relationship to hypothalamic-pituitary-adrenal (HPA) axis function prior to ethanol exposure. Monkeys were subjected to scheduled induction of ethanol consumption followed by free access to ethanol or water for 22 h/day over 12 months. Immunohistochemistry was performed using an anti-3α,5α-THP antibody. Prolonged voluntary drinking resulted in individual differences in ethanol consumption that ranged from 1.2 to 4.2 g/kg/day over 12 months. Prolonged ethanol consumption reduced cellular 3α,5α-THP immunoreactivity by 13 ± 2 percent (P < 0.05) in the lateral amygdala and 17 ± 2 percent (P < 0.05) in the basolateral amygdala. The effect of ethanol was most pronounced in heavy drinkers that consumed ≥3 g/kg ≥ 20 percent of days. Consequently, 3α,5α-THP immunoreactivity in both the lateral and basolateral amygdala was inversely correlated with average daily ethanol intake (Spearman r = -0.87 and -0.72, respectively, P < 0.05). However, no effect of ethanol and no correlation between drinking and 3α,5α-THP immunoreactivity were observed in the basomedial amygdala. 3α,5α-THP immunoreactivity following ethanol exposure was also correlated with HPA axis function prior to ethanol exposure. These data indicate that voluntary ethanol drinking reduces amygdala levels of 3α,5α-THP in non-human primates and that amygdala 3α,5α-THP levels may be linked to HPA axis function.
authors.affiliation: Department of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Beattie
authors.affiliation: Department of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Antoniette M
authors.initials: AM
authors.lastname: Maldonado-Devincci
authors.affiliation: Department of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Neuroscience Institute, National Research Council of Italy (CNR), Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Porcu
authors.affiliation: Department of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Todd K
authors.initials: TK
authors.lastname: O'Buckley
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Daunais
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Grant
authors.affiliation: Department of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: A Leslie
authors.initials: AL
authors.lastname: Morrow
mesh_terms: D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D008297:Male; D011280:Pregnanolone / Q000378:metabolism*; D012646:Self Administration
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol; D011280:Pregnanolone
keywords: Allopregnanolone; amygdala; chronic ethanol