Dalvi A, Rodgers R J
Ethopharmacology Laboratory, School of Psychology, University of Leeds, Leeds, LS2 9JT, UK.
Pharmacol Biochem Behav. 2001 Jan;68(1):23-32. doi: 10.1016/s0091-3057(00)00408-1.
Although it is widely believed that the anxiolytic effects of benzodiazepines are mediated through facilitation of GABA(A) receptor function, behavioural studies have to date provided rather weak support for this hypothesis. In particular, considerable inconsistency has been noted both for the effects of GABAergic manipulations in animal models of anxiety and the ability of GABA(A) receptor antagonists to block the anxiolytic effects of diazepam (DZ) and chlordiazepoxide. In view of the sensitivity of the murine plus-maze to the anxiety-modulating effects of GABAergic agents as well as classical benzodiazepines, the current study examined the extent to which the anxiolytic actions of valproic acid (VPA) and DZ in this test involve picrotoxin (PX)-sensitive receptor mechanisms. Subjects were male DBA/2 mice, test duration was 5 min, and ethological scoring methods were employed. Our results show that, while devoid of intrinsic behavioural effects under present test conditions, PX (0.25-0.5 mg/kg) selectively antagonised the anxiolytic-like (but not other) effects of VPA (400 mg/kg). In contrast, the same doses of PX failed to block any of the behavioural changes induced by DZ (1.5 mg/kg), including disinhibition of open arm exploration. These data suggest that the plus-maze anxiolytic effects of DZ in DBA/2 mice are not mediated through PX-sensitive GABA(A) receptors. Further studies will be required to assess the generality of present findings to other mouse strains, species and behavioural paradigms.
尽管人们普遍认为苯二氮䓬类药物的抗焦虑作用是通过促进GABA(A)受体功能介导的，但迄今为止，行为学研究对这一假说的支持相当薄弱。特别是，在焦虑动物模型中，GABA能操作的效果以及GABA(A)受体拮抗剂阻断地西泮（DZ）和氯氮䓬抗焦虑作用的能力都存在相当大的不一致性。鉴于小鼠高架十字迷宫对GABA能药物以及经典苯二氮䓬类药物的焦虑调节作用敏感，本研究考察了丙戊酸（VPA）和DZ在此测试中的抗焦虑作用在多大程度上涉及印防己毒素（PX）敏感的受体机制。实验对象为雄性DBA/2小鼠，测试持续时间为5分钟，并采用了行为学评分方法。我们的结果表明，虽然在当前测试条件下PX（0.25 - 0.5 mg/kg）本身没有行为学效应，但它能选择性地拮抗VPA（400 mg/kg）的抗焦虑样（而非其他）效应。相比之下，相同剂量的PX未能阻断DZ（1.5 mg/kg）诱导的任何行为变化，包括对开放臂探索的去抑制作用。这些数据表明，DZ对DBA/2小鼠的高架十字迷宫抗焦虑作用不是通过PX敏感的GABA(A)受体介导的。需要进一步研究来评估当前研究结果对其他小鼠品系、物种和行为范式的普遍性。
