Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates
Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates
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DOI：
10.1073/pnas.0405621102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Dawson, GR
中科院分区：
文献类型：
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作者：
Rowlett, JK;Platt, DM;Dawson, GR
苯二氮卓类药物通过与 GABA(A) 受体的多种亚型结合来发挥作用，大脑中的主要亚型是含有 α(1)-、α(2)-、α(3)- 和 α(5)- 亚基的亚型。为了了解这些亚型在苯二氮卓类药物治疗和副作用中的潜在不同作用，我们在非人灵长类动物模型中评估了 GABA(A) 受体亚型偏好化合物，预测苯二氮卓类药物的抗焦虑、镇静、运动、主观和增强作用。这些化合物包括唑吡坦，它优先结合含有 α(1) 亚基的 GABA(A) 受体（α(1)GABA(A) 受体）； L-838,417，其显示对α(2)GABA(A)、α(3)GABA(A)和α(5)GABA(A)受体的功能选择性；和非选择性传统苯二氮卓类药物。这些结果在非人类灵长类动物中提供了证据，证明 α(1)GABA(A) 受体在苯二氮卓类药物的抗焦虑和肌肉松弛特性中不起关键作用；相反，这些效应涉及 alpha(2)GABA(A)、alpha(3)GABA(A) 和/或 alpha(5)GABA(A) 亚型。我们的结果还表明，α(1)GABA(A) 受体亚型可能与苯二氮卓类药物的主观、镇静和运动作用密切相关。相反，刺激 α(1)GABA(A) 受体足以调节这些药物的滥用潜力，但不是必需的。
Benzodiazepines exert their effects by binding to multiple subtypes of the GABA(A) receptor, the predominant subtypes in the brain being those that contain alpha(1)-, alpha(2)-, alpha(3)-, and alpha(5)-subunits. To understand the potentially different roles of these subtypes in the therapeutic and side effects of benzodiazepines, we evaluated GABA(A) receptor subtype-pref erring compounds in nonhuman primate models predictive of anxiolytic, sedative, motor, subjective, and reinforcing effects of benzodiazepine-type drugs. These compounds included zolpidem, which shows preferential binding to GABA(A) receptors containing alpha(1)-subunits (alpha(1)GABA(A) receptors); L-838,417, which shows functional selectivity for alpha(2)GABA(A), alpha(3)GABA(A), and alpha(5)GABA(A) receptors; and nonselective conventional benzodiazepines. The results provide evidence in nonhuman primates that alpha(1)GABA(A) receptors do not play a key role in the anxiolytic and muscle-relaxant properties of benzodiazepine-type drugs; instead, these effects involve alpha(2)GABA(A), alpha(3)GABA(A), and/or alpha(5)GABA(A) subtypes. Our results also suggest that the alpha(1)GABA(A) receptor subtype might be critically involved in the subjective, sedative, and motor effects of benzodiazepine-type drugs. In contrast, stimulation of alpha(1)GABA(A) receptors is sufficient, but not necessary, for mediation of the abuse potential of these drugs.