WITHDRAWAL FROM 3-ALPHA-OH-5-ALPHA-PREGNAN-20-ONE USING A PSEUDOPREGNANCY MODEL ALTERS THE KINETICS OF HIPPOCAMPAL GABA(A)-GATED CURRENT AND INCREASES THE GABA(A), RECEPTOR ALPHA-4 SUBUNIT IN ASSOCIATION WITH INCREASED ANXIETY

In the present study, we have characterized properties of steroid with drawal using a pseudopregnant rat model. This paradigm results in incr eased production of endogenous progesterone from ovarian sources and a s such is a useful physiological model. ''Withdrawal'' from progestero ne induced by ovariectomy on day 12 of pseudopregnancy resulted in inc reased anxiety, as determined by a decrease in open arm entries on the elevated plus maze compared to control rats and pseudopregnant animal s not undergoing withdrawal. Similar findings were obtained 24 hr afte r administration of a 5 alpha-reductase blocker to a pseudopregnant an imal, suggesting that it is the GABA(A)-modulatory 3 alpha-OH-5 alpha- pregnan-20-one (3 alpha,5 alpha-THP) that produces anxiogenic withdraw al symptoms. Twenty-four hours after steroid withdrawal, the time cons tant for decay of GABA(A)-gated current was also reduced sixfold, asse ssed using whole-cell patch-clamp procedures on pyramidal neurons acut ely dissociated from CAI hippocampus. Thus, 3 alpha, 5 alpha-THP withd rawal results in a marked decrease in total GABA(A) current, a possibl e mechanism for its anxiogenic, proconvulsant sequelae. In addition, 3 alpha, 5 alpha-THP withdrawal resulted in insensitivity to the normal ly potentiating effect of the benzodiazepine lorazepam (LZM) on GABA(A )-gated Cl- current. This withdrawal profile is similar to that report ed for other GABA(A)-modulatory drugs such as the benzodiazepines (BDZ s), barbiturates, and ethanol. These changes were also associated with significant two and threefold increases in both the mRNA and protein for the alpha 4 subunit of the GABA(A) receptor, respectively, in hipp ocampus The pseudopregnancy paradigm may be a useful model for periods of endogenous 3 alpha, 5 alpha-THP withdrawal such as premenstrual sy ndrome and postpartum or postmenopausal dysphoria, when increased emot ional lability and BDZ insensitivity have been reported.