Journal of Neurophysiology, Vol 74, Issue 1 464-469, Copyright © 1995 by APS

ARTICLES

Withdrawal from the endogenous steroid progesterone results in GABAA currents insensitive to benzodiazepine modulation in rat CA1 hippocampus

A. M. Costa, K. T. Spence, S. S. Smith and J. M. ffrench-Mullen
Department of Pharmacology, Zeneca Pharmaceuticals, Wilmington, Delaware 19897, USA.

1. The withdrawal properties of the endogenous steroid progesterone (P) were tested in female rats as a function of benzodiazepine modulation of gamma-aminobutyric acid-A (GABAA)-gated current with the use of the whole cell patch-clamp technique on acutely dissociated CA1 hippocampal neurons. In a previous study, this steroid was shown to exhibit withdrawal properties, behaviorally. 2. One day withdrawal from in vivo administration of physiological doses of P (5 mg ip, 5 days/wk for 3 withdrawal cycles) or its metabolite, the GABAA modulator 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THP or allopregnanolone, 20 mg/kg ip) prevented the normally potentiating effect of lorazepam (LZM; 10(-7)-10(-4) M) on GABAA-gated current. Withdrawal from 500 micrograms P administered concomitantly with 2 micrograms 17 beta-estradiol also markedly diminished LZM potentiation of GABAA current. This effect was seen only after three withdrawal cycles. 3. P withdrawal produced no inhibitory effect on either basal levels of GABAA-evoked current, the GABAA EC50, or barbiturate (+/-Pentobarbital, 10(-7)-10(-4) M) modulation of this parameter. 4. The effect of steroid withdrawal on LZM modulation of GABAA-evoked current was blocked by picrotoxin as well as by indomethacin, a drug that prevents conversion of P to its metabolite, the GABAA modulator 3 alpha,5 alpha-THP. These results suggest that the withdrawal properties of P may be due to changes in GABAA receptor function produced by 3 alpha,5 alpha-THP.

This article has been cited by other articles:

				T. A. Lovick Plasticity of GABAA receptor subunit expression during the oestrous cycle of the rat: implications for premenstrual syndrome in women Exp Physiol, July 1, 2006; 91(4): 655 - 660. [Abstract] [Full Text] [PDF]

				F.-C. Hsu, R. Waldeck, D. S. Faber, and S. S. Smith Neurosteroid Effects on GABAergic Synaptic Plasticity in Hippocampus J Neurophysiol, April 1, 2003; 89(4): 1929 - 1940. [Abstract] [Full Text] [PDF]

				F.-C. Hsu and S. S. Smith Progesterone Withdrawal Reduces Paired-Pulse Inhibition in Rat Hippocampus: Dependence on GABAA Receptor alpha 4 Subunit Upregulation J Neurophysiol, January 1, 2003; 89(1): 186 - 198. [Abstract] [Full Text] [PDF]

				D. S. Reddy and M. A. Rogawski Chronic Treatment with the Neuroactive Steroid Ganaxolone in the Rat Induces Anticonvulsant Tolerance to Diazepam but Not to Itself J. Pharmacol. Exp. Ther., December 1, 2000; 295(3): 1241 - 1248. [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]

				A. G. Herzog Psychoneuroendocrine Aspects of Temporolimbic Epilepsy: Part I. Brain, Reproductive Steroids, and Emotions Psychosomatics, April 1, 1999; 40(2): 95 - 101. [Abstract] [Full Text]

				A. Concas, M. C. Mostallino, P. Porcu, P. Follesa, M. L. Barbaccia, M. Trabucchi, R. H. Purdy, P. Grisenti, and G. Biggio Role of brain allopregnanolone in the plasticity of gamma -aminobutyric acid type A receptor in rat brain during pregnancy and after delivery PNAS, October 27, 1998; 95(22): 13284 - 13289. [Abstract] [Full Text] [PDF]

				S. S. Smith, Q. H. Gong, X. Li, M. H. Moran, D. Bitran, C. A. Frye, and F.-C. Hsu Withdrawal from 3alpha -OH-5alpha -Pregnan-20-One Using a Pseudopregnancy Model Alters the Kinetics of Hippocampal GABAA-Gated Current and Increases the GABAA Receptor alpha 4 Subunit in Association with Increased Anxiety J. Neurosci., July 15, 1998; 18(14): 5275 - 5284. [Abstract] [Full Text] [PDF]