Withdrawal From the Endogenous Steroid Progesterone Results in GABA A
Currents Insensitive to Benzodiazepine Modulation in Rat CA1 Hippocampus.
Anna-Maria N. Costa, Katherine T. Spence, Sheryl S. Smith, Jarlath M.H.
ffrench-Mullen.
Dept. of Pharmacology, Zeneca Pharmaceuticals, Zeneca, Inc., Wilmington, DE
19897, U.S.A.; 2 Dept. of Anatomy and Neurobiology, MCP and Hahnemann
University, Philadelphia, PA 19102- 1192, U.S.A.
APStracts 2:0140N, 1995.
SUMMARY AND CONCLUSIONS
1. The withdrawal properties of the endogenous steroid progesterone (P) were
tested in female rats as a function of benzodiazepine modulation of GABA A -
gated current using 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, i.p., 5
days/week for 3 withdrawal cycles) or its metabolite, the GABA A modulator
3<F128>a<F255>- hydroxy-5<F128>a<F255>-pregnan- 20-one
(3<F128>a<F255>,5<F128>a<F255>-THP or allopregnanolone, 20
mg/kg, i.p.) prevented the normally potentiating effect of lorazepam (LZM; 10
-7 -10 -4 M) on GABA A -gated current. Withdrawal from 500<F128M>
m<F255D>g P administered concomitantly with 2<F128M> m<F255D>g 17
<F128>b<F255>-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 (<F128>ae<F255>-
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 which prevents conversion of P
to its metabolite, the GABA A modulator
3<F128>a<F255>,5<F128>a<F255>- THP. These results suggest that
the withdrawal properties of P may be due to changes in GABA A receptor
function produced by 3<F128>a<F255>,5<F128>a<F255>-THP.
Received 27 March 1994; accepted in final form 28 April 1995.
APS Manuscript Number J201-5.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 9 May 1995.