Sensitization of γ-aminobutyric acid(A) receptors to neuroactive steroids in rats during ethanol withdrawal

L. L. Devaud, R. H. Purdy, Deborah (Deb) Finn, A. L. Morrow

Research output: Contribution to journalArticle

168 Citations (Scopus)

Abstract

The anxiolytic and anticonvulsant effects of benzodiazepines, barbiturates, ethanol and neuroactive steroids are mediated by selective interactions with γ-aminobutyric acid(A) (GABA(A)) receptors. Chronic ethanol exposure decreases the sensitivity of GABA(A) receptors to benzodiazepines, barbiturates and ethanol. Ethanol withdrawing rats are cross-tolerant to the anticonvulsant effects of benzodiazepines as shown by a 16% decrease in the anticonvulsant efficacy of diazepam compared to controls. In contrast, ethanol withdrawing rats are sensitized to the anticonvulsant effects of the neuroactive steroid 3α-hydroxy-5α-pregnan-20-one (3α,5α- THP), exhibiting a 46% increase in the anticonvulsant effect against bicuculline-induced seizures compared to control rats. This effect may involve a change in the sensitivity of GABA(A) receptors to 3α,5α-THP because potentiation of GABA(A) receptor mediated chloride uptake into cerebral cortical synaptoneurosomes is enhanced by 3α,5α-THP up to 50% in ethanol withdrawing rats compared to controls. 3α,21-dihydroxy-5α-pregnan- 20-one (THDOC) potentiation of GABA(A) receptor-mediated chloride uptake is also enhanced during ethanol withdrawal. Moreover, the plasma levels of 3α,5α-THP and progesterone did not differ in ethanol withdrawing rats compared to controls. These alterations in neurosteroid sensitivity were also accompanied by selective alterations in cortical GABA(A) receptor subunit mRNA levels. Levels for the α1 and α4 subunit showed only slight alterations during withdrawal whereas we had previously observed a significant decrease in α1 and a significant increase in α4 mRNA levels in ethanol dependent (not withdrawing) animals. β2, β3 and γ1 mRNA levels significantly increased during ethanol withdrawal. Taken together, these results suggest that ethanol withdrawal produces alterations in GABA(A) receptors that sensitize rats to the pharmacological effects of neuroactive steroids. Because ethanol-dependent or withdrawing rats are tolerant to the intoxicating, anxiolytic and anticonvulsant effects of ethanol and cross- tolerant to many effects of benzodiazepines and barbiturates, sensitization to the effects of neuroactive steroids could have significant therapeutic potential.

Original languageEnglish (US)
Pages (from-to)510-517
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume278
Issue number2
StatePublished - 1996
Externally publishedYes

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Aminobutyrates
Ethanol
Steroids
GABA-A Receptors
Anticonvulsants
Benzodiazepines
Barbiturates
Anti-Anxiety Agents
Messenger RNA
Chlorides
Bicuculline
Diazepam
Progesterone
Neurotransmitter Agents

ASJC Scopus subject areas

  • Pharmacology

Cite this

Sensitization of γ-aminobutyric acid(A) receptors to neuroactive steroids in rats during ethanol withdrawal. / Devaud, L. L.; Purdy, R. H.; Finn, Deborah (Deb); Morrow, A. L.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 278, No. 2, 1996, p. 510-517.

Research output: Contribution to journalArticle

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abstract = "The anxiolytic and anticonvulsant effects of benzodiazepines, barbiturates, ethanol and neuroactive steroids are mediated by selective interactions with γ-aminobutyric acid(A) (GABA(A)) receptors. Chronic ethanol exposure decreases the sensitivity of GABA(A) receptors to benzodiazepines, barbiturates and ethanol. Ethanol withdrawing rats are cross-tolerant to the anticonvulsant effects of benzodiazepines as shown by a 16{\%} decrease in the anticonvulsant efficacy of diazepam compared to controls. In contrast, ethanol withdrawing rats are sensitized to the anticonvulsant effects of the neuroactive steroid 3α-hydroxy-5α-pregnan-20-one (3α,5α- THP), exhibiting a 46{\%} increase in the anticonvulsant effect against bicuculline-induced seizures compared to control rats. This effect may involve a change in the sensitivity of GABA(A) receptors to 3α,5α-THP because potentiation of GABA(A) receptor mediated chloride uptake into cerebral cortical synaptoneurosomes is enhanced by 3α,5α-THP up to 50{\%} in ethanol withdrawing rats compared to controls. 3α,21-dihydroxy-5α-pregnan- 20-one (THDOC) potentiation of GABA(A) receptor-mediated chloride uptake is also enhanced during ethanol withdrawal. Moreover, the plasma levels of 3α,5α-THP and progesterone did not differ in ethanol withdrawing rats compared to controls. These alterations in neurosteroid sensitivity were also accompanied by selective alterations in cortical GABA(A) receptor subunit mRNA levels. Levels for the α1 and α4 subunit showed only slight alterations during withdrawal whereas we had previously observed a significant decrease in α1 and a significant increase in α4 mRNA levels in ethanol dependent (not withdrawing) animals. β2, β3 and γ1 mRNA levels significantly increased during ethanol withdrawal. Taken together, these results suggest that ethanol withdrawal produces alterations in GABA(A) receptors that sensitize rats to the pharmacological effects of neuroactive steroids. Because ethanol-dependent or withdrawing rats are tolerant to the intoxicating, anxiolytic and anticonvulsant effects of ethanol and cross- tolerant to many effects of benzodiazepines and barbiturates, sensitization to the effects of neuroactive steroids could have significant therapeutic potential.",
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