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 modulation of gamma-aminobutyric acid-A (GABA(A))-gated current with the use of the whole cell patch-clamp technique on acutely dissociated CA1 hippocampal neurons. In a previous study, this steroid was shown to exhibit withdrawal properties, behaviorally. 2. One day withdrawal from in vivo 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 allopregnanolone, 20 mg/kg ip) prevented the normally potentiating effect of lorazepam (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 was seen only after three withdrawal cycles. 3. P withdrawal produced no 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 suggest that the withdrawal properties of P may be due to changes in GABA(A) receptor function produced by 3 alpha,5 alpha-THP.