title: Withdrawal from the endogenous steroid progesterone results in GABAA currents insensitive to benzodiazepine modulation in rat CA1 hippocampus.
abstract: 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 (GABAA)-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 GABAA 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 GABAA-gated current. Withdrawal from 500 micrograms P administered concomitantly with 2 micrograms 17 beta-estradiol also markedly diminished LZM potentiation of GABAA current. This effect was seen only after three withdrawal cycles. 3. P withdrawal produced no inhibitory effect on either basal levels of GABAA-evoked current, the GABAA EC50, or barbiturate (+/-Pentobarbital, 10(-7)-10(-4) M) modulation of this parameter. 4. The effect of steroid withdrawal on LZM modulation of GABAA-evoked current was blocked by picrotoxin as well as by indomethacin, a drug that prevents conversion of P to its metabolite, the GABAA modulator 3 alpha,5 alpha-THP. These results suggest that the withdrawal properties of P may be due to changes in GABAA receptor function produced by 3 alpha,5 alpha-THP.
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D008140:Lorazepam / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011280:Pregnanolone / Q000378:metabolism / Q000494:pharmacology; D011374:Progesterone / Q000009:adverse effects*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001569:Benzodiazepines; D018118:Chloride Channels; D018756:GABA Antagonists; D018757:GABA Modulators; D008140:Lorazepam; D010852:Picrotoxin; D011280:Pregnanolone; D011374:Progesterone; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid