Termination of pseudopregnancy in the rat produces an anxiogenic-like response that is associated with an increase in benzodiazepine receptor binding density and a decrease in GABA-stimulated chloride influx in the hippocampus

Abstract

The neurosteroid, 3alpha-OH-5alpha-pregnan-20-one (allopregnanolone) is a potent positive modulator of the GABA(A) receptor complex. Its pharmacological spectrum of action is shared by the benzodiazepines and alcohol, and includes anxiolytic, anticonvulsant, ataxic, and hypnotic effects. Discontinuation from chronic exposure to allopregnanolone or other neuroactive steroids has been shown to elicit behavioral effects that are typically seen in benzodiazepine or alcohol withdrawal. In this series of experiments, the effects of an endogenous elevation of ovarian steroids on brain GABA(A) receptor function was examined by inducing pseudopregnancy. In female rats, pseudopregnancy did not affect behavior in the elevated plus-maze, despite a persistent increase in circulating levels of allopregnanolone. Pseudopregnancy was associated with a decrease in the maximal binding density of 3H-flunitrazepam in the cerebral cortex and cerebellum; however, GABA-stimulated chloride influx in cerebral cortical, hippocampal, and cerebellar synaptoneurosomes remained unaffected during pseudopregnancy. Termination of pseudopregnancy by ovariectomy precipitated an anxiogenic-like effect in the elevated plus-maze. The withdrawal from elevated ovarian steroid levels also increased the number of benzodiazepine receptors and decreased GABA-stimulated chloride influx in the hippocampus.