Moran M H, Goldberg M, Smith S S
Department of Neurobiology and Anatomy, EPPI, 3200 Henry Ave., Allegheny University of the Health Sciences, Philadelphia, PA 19129, USA.
Brain Res. 1998 Oct 5;807(1-2):91-100. doi: 10.1016/s0006-8993(98)00781-1.
Previous results from this lab have demonstrated that the GABA-modulatory steroid 3alpha-OH-5alpha-pregnan-20-one (3alpha, 5alpha-THP) exhibits withdrawal properties, increasing anxiety [M.A. Gallo, S.S. Smith, Progesterone withdrawal decreases latency to and increases duration of electrified prod burial: a possible rat model of PMS anxiety, Pharmacol. 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, GABAA receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid, Nature 392 (1998) 926-930.] upon abrupt discontinuation after chronic administration of its parent compound, progesterone (P), in a manner similar to other GABA-modulatory drugs. Further, we have demonstrated that withdrawal from P produces insensitivity to the potentiating effects of the benzodiazepine (BDZ) lorazepam (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 steroid progesterone results in GABAA currents insensitive to BDZ modulation 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, GABAA receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid, Nature 392 (1998) 926-930.], assessed using whole cell patch clamp procedures on pyramidal neurons acutely dissociated from CA1 hippocampus. The purpose of the present study was to examine the withdrawal effects of P on the sedative potency of LZM, tested behaviorally as the ability to maintain position on a variable speed treadmill following LZM administration (0.75 mg/kg). Both continuous (continuous release P capsule, single withdrawal) as well as discontinuous (multiple P injection, multiple withdrawal) paradigms 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 multiple withdrawal paradigm was prevented by prior intraventricular administration of antisense oligonucleotide against the alpha4 subunit of the GABAA receptor. These results support the hypothesis that withdrawal from P decreases the behavioral response to LZM as a direct result of increases in the alpha4 subunit of the GABAA receptor. Withdrawal from P occurs endogenously during pre-menstrual and post-partum periods, when decreased response to BDZ has been reported.
该实验室之前的研究结果表明，γ-氨基丁酸调节性类固醇3α-羟基-5α-孕烷-20-酮（3α, 5α-四氢孕酮）具有戒断特性，会增加焦虑感[M.A. 加洛、S.S. 史密斯，孕酮戒断会缩短电击足底掩埋潜伏期并延长其持续时间：经前期综合征焦虑的一种可能大鼠模型，《药理学与生物化学》46 (1993) 897 - 904]，并且在长期给予其母体化合物孕酮（P）后突然停药时，会增加癫痫易感性[S.S. 史密斯、Q.H. 龚、F.-C. 许、R.S. 马克维茨、J.M.H. 弗伦奇 - 马伦、X. 李，γ-氨基丁酸A受体α4亚基抑制可防止内源性类固醇的戒断特性，《自然》392 (1998) 926 - 930]，其方式与其他γ-氨基丁酸调节性药物类似。此外，我们已经证明，从P戒断会导致对苯二氮䓬类药物（BDZ）劳拉西泮（LZM）增强γ-氨基丁酸门控氯离子电流的作用产生不敏感性[A.-M.N. 科斯塔、K.T. 斯彭斯、S.S. 史密斯、J.M.H. 弗伦奇 - 马伦，内源性类固醇孕酮戒断导致大鼠CA1海马区γ-氨基丁酸A电流对BDZ调节不敏感，《神经生理学杂志》74 (1995) 464 - 469；S.S. 史密斯、Q.H. 龚、F.-C. 许、R.S. 马克维茨、J.M.H. 弗伦奇 - 马伦、X. 李，γ-氨基丁酸A受体α4亚基抑制可防止内源性类固醇的戒断特性，《自然》392 (1998) 926 - 930]，这是通过对急性分离自CA1海马区的锥体神经元使用全细胞膜片钳技术进行评估的。本研究的目的是检查P戒断对LZM镇静效力的影响，通过行为学测试，即给予LZM（0.75 mg/kg）后在变速跑步机上保持姿势的能力来进行检测。连续（持续释放P胶囊，单次戒断）以及间断（多次注射P，多次戒断）范式均进行了测试。更长时间的持续释放范式在消除LZM的镇静作用方面更有效，且不会改变基线反应。在多次戒断范式后观察到的LZM不敏感性可通过预先脑室内注射针对γ-氨基丁酸A受体α4亚基的反义寡核苷酸来预防。这些结果支持了这样一种假说，即从P戒断会降低对LZM的行为反应，这是γ-氨基丁酸A受体α4亚基增加的直接结果。在经前期和产后内源性地会发生从P的戒断，此时已有报道称对BDZ的反应会降低。
