Withdrawal from the endogenous steroid progesterone results in GABAA currents insensitive to benzodiazepine modulation in rat CA1 hippocampus

J Neurophysiol. 1995 Jul;74(1):464-9. doi: 10.1152/jn.1995.74.1.464.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzodiazepines / pharmacology*
  • Brain Chemistry / drug effects
  • Chloride Channels / drug effects
  • Chloride Channels / metabolism
  • Electrophysiology
  • Female
  • GABA Antagonists / pharmacology
  • GABA Modulators / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Ion Channel Gating / drug effects
  • Lorazepam / pharmacology
  • Picrotoxin / pharmacology
  • Pregnanolone / metabolism
  • Pregnanolone / pharmacology
  • Progesterone / adverse effects*
  • Rats
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / metabolism*
  • Substance Withdrawal Syndrome / metabolism*
  • gamma-Aminobutyric Acid / metabolism


  • Chloride Channels
  • GABA Antagonists
  • GABA Modulators
  • Receptors, GABA-A
  • Picrotoxin
  • Benzodiazepines
  • Progesterone
  • gamma-Aminobutyric Acid
  • Pregnanolone
  • Lorazepam