Ojima K, Matsumoto K, Watanabe H
Department of Pharmacology, Research Institute for Wakan-Yaku (Oriental Medicines), Toyama Medical and Pharmaceutical University, Japan.
Brain Res. 1997 Jan 16;745(1-2):127-33. doi: 10.1016/s0006-8993(96)01136-5.
Long-term social isolation stress has been shown to cause a decrease in pentobarbital (PB)-induced sleeping time in mice. In the present study, to clarify whether the GABAA/benzodiazepine (BZD) receptor system is involved in the decrease in the hypnotic activity of PB by social isolation stress, we examined the effects of BZD receptor ligands on the PB-induced sleep in group-housed and socially isolated mice. Moreover, we also tested whether social isolation stress affects the ability of GABA to stimulate 36Cl- uptake or the modulatory effect of diazepam and PB and GABA-induced stimulation of 36Cl- uptake into synaptoneurosomes prepared from mouse brain. Social isolation stress significantly decreased the PB-induced sleeping time in mice. The BZD receptor diazepam (0.1-0.8 mg/kg, i.p.) dose-dependently prolonged PB sleep in group-housed and isolated mice, but the effect was weaker in isolated mice. In contrast, FG7142 (5-10 mg/kg, i.p.), a BZD receptor inverse agonist, shortened the sleep in group-housed but not in isolated mice. Flumazenil (16.5-33 nmol, i.c.v.), a selective BZD receptor antagonist, caused PB sleep in isolated mice to return to the level of group-housed mice, at the dose that antagonized the effects of diazepam and FG7142 on PB sleep in group-housed mice. However, this antagonist alone produced no effect on PB sleep in group-housed mice. Social isolation stress decreased the ability of GABA (0.6-200 microM) to stimulate 36Cl- uptake into synaptoneurosomes but this stress had no effect on PB- and diazepam-induced enhancement of GABA-stimulated 36Cl- uptake. These results suggest that endogenous substance(s) with an inverse BZD receptor agonist-like property and the changes in the ability of GABA to stimulate chloride ion channels are involved in the decrease in the hypnotic activity of pentobarbital following social isolation stress.
长期的社会隔离应激已被证明会导致小鼠戊巴比妥（PB）诱导的睡眠时间减少。在本研究中，为了阐明γ-氨基丁酸A型/苯二氮䓬（BZD）受体系统是否参与社会隔离应激导致的PB催眠活性降低，我们研究了BZD受体配体对群居和社会隔离小鼠PB诱导睡眠的影响。此外，我们还测试了社会隔离应激是否会影响γ-氨基丁酸（GABA）刺激氯离子摄取的能力，以及地西泮、PB和GABA诱导的刺激从小鼠脑制备的突触体摄取氯离子的调节作用。社会隔离应激显著降低了小鼠PB诱导的睡眠时间。BZD受体地西泮（0.1 - 0.8mg/kg，腹腔注射）剂量依赖性地延长了群居和隔离小鼠的PB睡眠时间，但在隔离小鼠中的作用较弱。相反，BZD受体反向激动剂FG7142（5 - 10mg/kg，腹腔注射）缩短了群居小鼠的睡眠时间，但对隔离小鼠没有影响。氟马西尼（16.5 - 33nmol，脑室内注射），一种选择性BZD受体拮抗剂，在拮抗地西泮和FG7142对群居小鼠PB睡眠影响的剂量下，使隔离小鼠的PB睡眠恢复到群居小鼠的水平。然而，单独使用这种拮抗剂对群居小鼠的PB睡眠没有影响。社会隔离应激降低了GABA（0.6 - 200μM）刺激突触体摄取氯离子的能力，但这种应激对PB和地西泮诱导的GABA刺激氯离子摄取的增强没有影响。这些结果表明，具有反向BZD受体激动剂样性质的内源性物质以及GABA刺激氯离子通道能力的变化参与了社会隔离应激后戊巴比妥催眠活性的降低。
