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The Journal of Neuroscience, July 15, 1998, 18(14):5275-5284

Withdrawal from 3-OH-5-Pregnan-20-One Using a Pseudopregnancy Model Alters the Kinetics of Hippocampal GABA_A-Gated Current and Increases the GABA_A Receptor 4 Subunit in Association with Increased Anxiety

Sheryl S. Smith¹, Qi H. Gong¹, Xinshe Li¹, Maria H. Moran¹, Daniel Bitran², Cheryl A. Frye³, and Fu-Chun Hsu¹

¹ Department of Neurobiology and Anatomy, Allegheny University of the Health Sciences, Eastern Pennsylvania Psychiatric Institute, Philadelphia, Pennsylvania 19129, ²  Department of Psychology, College of the Holy Cross, Worcester, Massachusetts 01610, and ³ Department of Psychology, The University of Albany, State University of New York, Albany, New York 12222

In the present study, we have characterized properties of steroid withdrawal using a pseudopregnant rat model. This paradigm results in increased production of endogenous progesterone from ovarian sources and as such is a useful physiological model. "Withdrawal" from progesterone induced by ovariectomy on day 12 of pseudopregnancy resulted in increased anxiety, as determined by a decrease in open arm entries on the elevated plus maze compared to control rats and pseudopregnant animals not undergoing withdrawal. Similar findings were obtained 24 hr after administration of a 5-reductase blocker to a pseudopregnant animal, suggesting that it is the GABA_A-modulatory 3-OH-5-pregnan-20-one (3,5-THP) that produces anxiogenic withdrawal symptoms. Twenty-four hours after steroid withdrawal, the time constant for decay of GABA_A-gated current was also reduced sixfold, assessed using whole- cell patch-clamp procedures on pyramidal neurons acutely dissociated from CA1 hippocampus. Thus, 3,5-THP withdrawal results in a marked decrease in total GABA_A current, a possible mechanism for its anxiogenic, proconvulsant sequelae. In addition, 3,5-THP withdrawal resulted in insensitivity to the normally potentiating effect of the benzodiazepine lorazepam (LZM) on GABA_A-gated Cl current. This withdrawal profile is similar to that reported for other GABA_A-modulatory drugs such as the benzodiazepines (BDZs), barbiturates, and ethanol. These changes were also associated with significant two and threefold increases in both the mRNA and protein for the 4 subunit of the GABA_A receptor, respectively, in hippocampus. The pseudopregnancy paradigm may be a useful model for periods of endogenous 3,5-THP withdrawal such as premenstrual syndrome and postpartum or postmenopausal dysphoria, when increased emotional lability and BDZ insensitivity have been reported.

Key words: GABA_A receptor; rat; allopregnanolone; progesterone; -4 subunit; decay time constant; elevated plus maze; kinetics; GABA_A-gated current

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18145275-10$05.00/0

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