Abstract
Positive modulation of GABAA and antagonism of N-methyl-d-aspartate receptors mediate the discriminative stimulus effects of ethanol. Endogenous neuroactive steroids produce effects similar to ethanol, suggesting that these steroids may modulate ethanol addiction. The four isomers of the functional esters at C-3 of the 3-hydroxy metabolites of 4-pregnene-3,20-dione (progesterone) [allopregnanolone (3α,5α-P), pregnanolone (3α,5β-P), epiallopregnanolone (3β,5α-P), and epipregnanolone (3β,5β-P)], a synthetic analog of steroids modified by endogenous sulfation [pregnanolone hemisuccinate (3α,5β-P HS)], and a structurally similar, adrenally derived steroid [3α-hydroxy-5-androstan-17-one (3α,5α-A, androsterone)] were assessed for ethanol-like discriminative stimulus effects at 30 or 60 min after administration in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 or 2.0 g/kg ethanol (i.g.) with a 30-min pretreatment interval. The 3α-hydroxysteroids completely substituted for ethanol (80% of cases), whereas the 3β-hydroxysteroids and 3α,5β-P HS rarely substituted for ethanol (6% of cases). There were no sex differences. Compared with monkeys trained to discriminate 2.0 g/kg ethanol, 3α,5β-P and 3α,5α-A substituted more potently in monkeys trained to discriminate 1.0 g/kg ethanol. Compared with the 5β-reduced isomer (3α,5β-P), the 5α isomer of pregnanolone (3α,5α-P) substituted for ethanol with 3 to 40-fold greater potency but was least efficacious in female monkeys trained to discriminate 2.0 g/kg ethanol. The data suggest that the discriminative stimulus effects of lower doses (1.0 g/kg) of ethanol are mediated to a greater extent by 3α,5β-P- and 3α,5α-A-sensitive receptors compared with higher doses (2.0 g/kg). Furthermore, the discriminative stimulus effects of ethanol appear to be mediated by activity at binding sites that are particularly sensitive to 3α,5α-P.
Footnotes
-
This work was funded by NIAAA, National Institutes of Health Grants AA10009, AA 13860, and RR 000163. This work was presented at the 30th Annual Meeting of the Research Society on Alcoholism; 2007 Jul 7–11; Chicago, IL. Research Society on Alcoholism, Austin, TX (Helms CM et al. (2007) Neurosteroid-like discriminative stimulus effects of ethanol in monkeys are influenced by C-3 steroidal stereochemistry and ionic charge of esters. Alcohol Clin Exp Res31 (Suppl):80A).
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.108.137315.
-
ABBREVIATIONS: NMDA, N-methyl-d-aspartate; DHEA, dehydroepiandrosterone; FR, fixed ratio; ANOVA, analysis of variance; 3α,5α-P, allopregnanolone; 3α,5β-P, pregnanolone; 3β,5α-P, epiallopregnanolone; 3β,5β-P, epipregnanolone; 3α,5β-P HS, pregnanolone hemisuccinate; 3α,5α-A, androsterone.
-
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received February 1, 2008.
- Accepted April 23, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|