WITHDRAWAL FROM THE ENDOGENOUS STEROID PROGESTERONE RESULTS IN GABA(A) CURRENTS INSENSITIVE TO BENZODIAZEPINE MODULATION IN RAT CA1 HIPPOCAMPUS

1. The withdrawal properties of the endogenous steroid progesterone (P ) were tested in female rats as a function of benzodiazepine modulatio n of gamma-aminobutyric acid-A (GABA(A))-gated current with the use of the whole cell patch-clamp technique on acutely dissociated CA1 hippo campal neurons. In a previous study, this steroid was shown to exhibit withdrawal properties, behaviorally. 2. One day withdrawal from in vi vo administration of physiological doses of P (5 mg ip, 5 days/wk for 3 withdrawal cycles) or its metabolite, the GABA(A) modulator 3 alpha- hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THP or allopregnanolon e, 20 mg/kg ip) prevented the normally potentiating effect of lorazepa m (LZM; 10(-7)-10(-4) M) on GABA(A)-gated current. Withdrawal from 500 mu g P administered concomitantly with 2 mu g 17 beta-estradiol also markedly diminished LZM potentiation of GABA(A) current. This effect w as seen only after three withdrawal cycles. 3. P withdrawal produced n o inhibitory effect on either basal levels of GABA(A)-evoked current, the GABA(A) EC(50), or barbiturate (+/--Pentobarbital, 10(-7)-10(-4) M ) modulation of this parameter. 4. The effect of steroid withdrawal on LZM modulation of GABA(A)-evoked current was blocked by picrotoxin as well as by indomethacin, a drug that prevents conversion of P to its metabolite, the GABA(A) modulator 3 alpha,5 alpha-THP. These results s uggest that the withdrawal properties of P may be due to changes in GA BA(A) receptor function produced by 3 alpha,5 alpha-THP.