Amn. Costa et al., WITHDRAWAL FROM THE ENDOGENOUS STEROID PROGESTERONE RESULTS IN GABA(A) CURRENTS INSENSITIVE TO BENZODIAZEPINE MODULATION IN RAT CA1 HIPPOCAMPUS, Journal of neurophysiology, 74(1), 1995, pp. 464-469
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.