Matsumoto K, Ojima K, Watanabe H
Division of Pharmacology, Toyama Medical and Pharmaceutical University, Japan.
Brain Res. 1996 Feb 5;708(1-2):1-6. doi: 10.1016/0006-8993(95)01277-x.
Stressful manipulations are known to change the level of neurosteroids capable of interacting with GABAA receptor in the brain. To clarify the involvement of these neurosteroids in social isolation stress-induced decrease in pentobarbital sleep in mice, we examined the effects of 3 beta-hydroxy-5-pregnen-20-one-3-sulfate (pregnenolone sulfate, PS), a steroidal GABAA antagonist, and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allo-THDOC) and 3 alpha,21-dihydroxy-5 beta-pregnan-20-one (THDOC), positive allosteric modulators of the GABAA receptor, on the hypnotic activity of pentobarbital in socially isolated mice. Pentobarbital (50 mg/kg, i.p.)-induced sleep was significantly shorter in isolated mice than in group-housed mice and adrenalectomy had no effect on the decrease of pentobarbital sleep following social isolation. PS (5-10 mg/kg, i.p. or 12-24 nmol, i.c.v.) decreased pentobarbital sleep in group-housed mice in a dose-dependent manner without affecting the sleep in socially isolated mice. In contrast, allo-THDOC (14.9-37.4 nmol, i.c.v.) and THDOC (5-12.5 mg/kg, i.p. or 14.9-37.4 nmol, i.c.v.) reversed the pentobarbital sleep decreased by social isolation to the level in group-housed mice. These steroids had no effect on the pentobarbital sleep in group-housed mice. Such a reversing effect of THDOC in isolated mice was significantly blocked by PS (24 nmol, i.c.v.). Moreover, i.c.v. injection of yohimbine (30 nmol), methoxamine (200 nmol) and CRF (2.1 nmol) significantly decreased pentobarbital sleep in group-housed mice but not that in isolated mice. The effects of these drugs on pentobarbital sleep in group-housed mice were significantly attenuated by THDOC (12.5 mg/kg, i.p.). These results suggest that changes in the level of neurosteroids with ability to modulate GABAA receptor function are involved in social isolation-induced decrease in the hypnotic activity of pentobarbital in mice.
已知应激性操作会改变大脑中能够与GABAA受体相互作用的神经甾体水平。为了阐明这些神经甾体在社会隔离应激诱导的小鼠戊巴比妥睡眠减少中的作用，我们研究了甾体GABAA拮抗剂3β-羟基-5-孕烯-20-酮-3-硫酸盐（孕烯醇酮硫酸盐，PS）以及GABAA受体的正变构调节剂3α,21-二羟基-5α-孕烷-20-酮（别孕烷醇酮）和3α,21-二羟基-5β-孕烷-20-酮（孕烷醇酮）对社会隔离小鼠中戊巴比妥催眠活性的影响。戊巴比妥（50 mg/kg，腹腔注射）诱导的睡眠在隔离小鼠中比群居小鼠明显更短，并且肾上腺切除术对社会隔离后戊巴比妥睡眠的减少没有影响。PS（5 - 10 mg/kg，腹腔注射或12 - 24 nmol，脑室内注射）以剂量依赖的方式减少群居小鼠的戊巴比妥睡眠，而不影响社会隔离小鼠的睡眠。相反，别孕烷醇酮（14.9 - 37.4 nmol，脑室内注射）和孕烷醇酮（5 - 12.5 mg/kg，腹腔注射或14.9 - 37.4 nmol，脑室内注射）将社会隔离导致的戊巴比妥睡眠减少逆转至群居小鼠的水平。这些甾体对群居小鼠的戊巴比妥睡眠没有影响。孕烷醇酮在隔离小鼠中的这种逆转作用被PS（24 nmol，脑室内注射）显著阻断。此外，脑室内注射育亨宾（30 nmol）、甲氧明（200 nmol）和促肾上腺皮质激素释放因子（2.1 nmol）显著减少群居小鼠的戊巴比妥睡眠，但不影响隔离小鼠的睡眠。这些药物对群居小鼠戊巴比妥睡眠的影响被孕烷醇酮（12.5 mg/kg，腹腔注射）显著减弱。这些结果表明，具有调节GABAA受体功能能力的神经甾体水平变化参与了社会隔离诱导的小鼠戊巴比妥催眠活性降低。
