PROGESTERONE WITHDRAWAL II - INSENSITIVITY TO THE SEDATIVE EFFECTS OFA BENZODIAZEPINE

Previous results from this lab have demonstrated that the GABA-modulat ory steroid 3 alpha-OH-5 alpha-pregnan-20-one (3 alpha,5 alpha-THP) ex hibits withdrawal properties, increasing anxiety [M.A. Gallo, S.S. Smi th, Progesterone withdrawal decreases latency to and increases duratio n of electrified prod burial: a possible rat model of PMS anxiety, Pha rmacol. Biochem. 46 (1993) 897-904.] and seizure susceptibility [S.S. Smith, Q.H. Gong, F.-C. Hsu, R.S. Markowitz, J.M.H. ffrench-Mullen, X. Li, GABA(A) receptor alpha 4 subunit suppression prevents withdrawal properties of an endogenous steroid, Nature 392 (1998) 926-930.] upon abrupt discontinuation after chronic administration of its parent comp ound, progesterone (P), in a manner similar to other GABA-modulatory d rugs. Further, we have demonstrated that withdrawal from P produces in sensitivity to the potentiating effects of the benzodiazepine (BDZ) lo razepam (LZM) on GABA-gated Cl- current [A.-M.N. Costa, K.T. Spence, S .S. Smith, J.M.H. ffrench-Mullen, Withdrawal from the endogenous stero id progesterone results in GABA(A) currents insensitive to BDZ modulat ion in rats CA1 hippocampus, J. Neurophysiology 74 (1995) 464-469; S.S . Smith, Q.H. Gong, F.-C. Hsu, R.S. Markowitz, J.M.H. ffrench-Mullen, X. Li, GABA(A) receptor alpha 4 subunit suppression prevents withdrawa l properties of an endogenous steroid, Nature 392 (1998) 926-930.], as sessed using whole cell patch clamp procedures on pyramidal neurons ac utely dissociated from CA1 hippocampus. The purpose of the present stu dy was to examine the withdrawal effects of P on the sedative potency of LZM, tested behaviorally as the ability to maintain position on a v ariable speed treadmill following LZM administration (0.75 mg/kg). Bot h continuous (continuous release P capsule, single withdrawal) as well as discontinuous (multiple P injection, multiple withdrawal) paradigm s were tested. Longer continuous release paradigms were more effective in abolishing the sedative effects of LZM, without producing a change in baseline response. The LZM insensitivity observed following the mu ltiple withdrawal paradigm was prevented by prior intraventricular adm inistration of antisense oligonucleotide against the alpha 4 subunit o f the GABA(A) receptor. These results support the hypothesis that with drawal from P decreases the behavioral response to LZM as a direct res ult of increases in the alpha 4 subunit of the GABA(A) receptor. Withd rawal from P occurs endogenously during pre-menstrual and post-partum periods, when decreased response to BDZ has been reported. (C) 1998 El sevier Science B.V. All rights reserved.