Termination of pseudopregnancy in the rat alters the response to progesterone, chlordiazepoxide, and MK-801 in the elevated plus-maze

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Abstract
Allopregnanolone, a neurosteroid-reduced metabolite of progesterone, is a well-documented positive modulator of the γ-aminobutyric type A (GABAA) receptor. As has been reported for other positive modulators of the GABAA receptor, chronic exposure to neurosteroids is hypothesized to decrease GABAA receptor function. Drawing from the literature on chronic exposure to benzodiazepines or alcohol, putative changes in N-methyl-d-aspartate (NMDA) receptor function are also expected after chronic neurosteroid exposure. To assess the sensitivity of the GABAA and NMDA receptors after chronic elevation of neurosteroid produced by termination of pseudopregnancy in behavioral tests of anxiety and sensorimotor coordination. Female rats ovariectomized on day 10 of pseudopregnancy were tested in the elevated plus-maze and on the rotor rod after an acute injection of progesterone (4 mg/0.2 ml, s.c.), chlordiazepoxide (5 or 15 mg/kg, i.p.), or MK-801 (0.025, 0.05, or 0.1 mg/kg, i.p.). Pseudopregnancy termination produced an anxiogenic-like response in the plus-maze; an acute injection of progesterone restored baseline levels of behavior in this test. Pseudopregnancy termination eliminated the anxiolytic-like, sedative, and ataxic effects of chlordiazepoxide. In contrast, pseudopregnancy termination produced an increased sensitivity to the anxiolytic-like and ataxic effects of MK-801. The effects of pseudopregnancy termination on the behavioral response to positive modulators of the GABAA receptor are consistent with results from studies in which chronic exposure to neurosteroids decreases the response to acute neurosteroid and benzodiazepine administration. However, unlike the enhanced glutamatergic tone resulting from discontinuation of chronic benzodiazepine or alcohol exposure, the termination of pseudopregnancy apparently decreases NMDA receptor function.