Sensitization of gamma-aminobutyric acidA receptors to neuroactive steroids in rats during ethanol withdrawal

LL Devaud, RH Purdy, DA Finn and AL Morrow

Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, USA.

The anxiolytic and anticonvulsant effects of benzodiazepines, barbiturates, ethanol and neuroactive steroids are mediated by selective interactions with gamma-aminobutyric acidA (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 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-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 3 alpha,5 alpha-THP because potentiation of GABA(A) receptor mediated chloride uptake into cerebral cortical synaptoneurosomes is enhanced by 3 alpha,5 alpha-THP up to 50% in ethanol withdrawing rats compared to controls. 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (THDOC) potentiation of GABA(A) receptor-mediated chloride uptake is also enhanced during ethanol withdrawal. Moreover, the plasma levels of 3 alpha,5 alpha-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 alpha 1 and alpha 4 subunit showed only slight alteration during withdrawal whereas we had previously observed a significant decrease in alpha 1 and a significant increase in alpha 4 mRNA levels in ethanol dependent (not withdrawing) animals. beta 2, beta and gamma 1 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.

Volume 278, Issue 2, pp. 510-517, 08/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				P. E. Alele and L. L. Devaud Sex Differences in Steroid Modulation of Ethanol Withdrawal in Male and Female Rats J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 427 - 436. [Abstract] [Full Text] [PDF]

				J. K. Staley, C. Gottschalk, I. L. Petrakis, R. Gueorguieva, S. O'Malley, R. Baldwin, P. Jatlow, N. P. L. G. Verhoeff, E. Perry, D. Weinzimmer, et al. Cortical {gamma}-Aminobutyric Acid Type A-Benzodiazepine Receptors in Recovery From Alcohol Dependence: Relationship to Features of Alcohol Dependence and Cigarette Smoking Arch Gen Psychiatry, August 1, 2005; 62(8): 877 - 888. [Abstract] [Full Text] [PDF]

				J. Liang, E. Cagetti, R. W. Olsen, and I. Spigelman Altered Pharmacology of Synaptic and Extrasynaptic GABAA Receptors on CA1 Hippocampal Neurons Is Consistent with Subunit Changes in a Model of Alcohol Withdrawal and Dependence J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1234 - 1245. [Abstract] [Full Text] [PDF]

				E. Sanna, M. C. Mostallino, F. Busonero, G. Talani, S. Tranquilli, M. Mameli, S. Spiga, P. Follesa, and G. Biggio Changes in GABAA Receptor Gene Expression Associated with Selective Alterations in Receptor Function and Pharmacology after Ethanol Withdrawal J. Neurosci., December 17, 2003; 23(37): 11711 - 11724. [Abstract] [Full Text] [PDF]

				J. E. Kralic, M. Wheeler, K. Renzi, C. Ferguson, T. K. O'Buckley, A. C. Grobin, A. L. Morrow, and G. E. Homanics Deletion of GABAA Receptor alpha 1 Subunit-containing Receptors Alters Responses to Ethanol and Other Anesthetics J. Pharmacol. Exp. Ther., May 1, 2003; 305(2): 600 - 607. [Abstract] [Full Text] [PDF]

				E. Cagetti, J. Liang, I. Spigelman, and R. W. Olsen Withdrawal from Chronic Intermittent Ethanol Treatment Changes Subunit Composition, Reduces Synaptic Function, and Decreases Behavioral Responses to Positive Allosteric Modulators of GABAA Receptors Mol. Pharmacol., January 1, 2003; 63(1): 53 - 64. [Abstract] [Full Text] [PDF]

				E. Malatynska, W. Dyr, P. Krzascik, and W. Kostowski Changes in ethanol preference by rats treated with {gamma}1 and {gamma}2 GABAA receptor subunit antisense oligodeoxynucleotides Alcohol Alcohol., July 1, 2001; 36(4): 309 - 313. [Abstract] [Full Text] [PDF]

				D. S. Reddy and M. A. Rogawski Enhanced Anticonvulsant Activity of Ganaxolone after Neurosteroid Withdrawal in a Rat Model of Catamenial Epilepsy J. Pharmacol. Exp. Ther., September 1, 2000; 294(3): 909 - 915. [Abstract] [Full Text]

				M. J. VanDoren, D. B. Matthews, G. C. Janis, A. C. Grobin, L. L. Devaud, and A. L. Morrow Neuroactive Steroid 3alpha -Hydroxy-5alpha -Pregnan-20-One Modulates Electrophysiological and Behavioral Actions of Ethanol J. Neurosci., March 1, 2000; 20(5): 1982 - 1989. [Abstract] [Full Text] [PDF]

				D. A. Finn, E. J. Gallaher, and J. C. Crabbe Differential Change in Neuroactive Steroid Sensitivity during Ethanol Withdrawal J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 394 - 405. [Abstract] [Full Text]

				R. A. Harris, C. F. Valenzuela, S. Brozowski, L. Chuang, K. Hadingham, and P. J. Whiting Adaptation of gamma -Aminobutyric Acid Type A Receptors to Alcohol Exposure: Studies with Stably Transfected Cells J. Pharmacol. Exp. Ther., January 1, 1998; 284(1): 180 - 188. [Abstract] [Full Text]