作用于GABAA受体的药物与神经可塑性

摘要/Abstract

摘要： GABAA受体介导中枢神经递质GABA产生快速抑制反应，是治疗焦虑障碍、失眠和麻醉重要药物靶点。但是长期使用这些药物，可产生耐受和成瘾发生的风险。机制可能为引起大脑反馈回路的异常神经适应。目前，已证明苯二氮?类作用的突触GABAA受体和突触外GABAA受体的调节剂(THIP和神经甾体)已证明可以诱发腹侧被盖区多巴胺神经元的可塑性。此外，不同突触或突触外GABAA受体激活的数量和重复用药均与神经调节的奖励和厌恶反应（reward and aversion）相关。作用于突触和突触外GABAA受体的药物均可抑制VTA的GABAA能中间神经元，从而激活VTA区DA能神经元，由此去抑制和诱导谷氨酸能神经的突触可塑性。尽管此类药物未能改变突触棘数量，却能抑制脑代谢和基因表达，其诱导成熟神经元的神经可塑性的可能方式是：解除主要神经元抑制作用；这一观点仍有待验证。

关键词: GABAA受体, 苯二氮?类, 树突棘, 多巴胺神经元, 神经适应, 神经甾体

Abstract: GABAA receptors are the fast inhibitory neurotransmitter receptors, which are important targets for drugs used in the treatment of anxiety disorders, insomnia and anesthesia. while, there are significant risks after the long-time use of these drugs, particularly in tolerance and addiction. Recent findings suggested that those drugs may induce aberrant neuroadaptations in the brain reward circuitry. Recently, benzodiazepines, acting on synaptic GABAA receptors, and modulators of extrasynaptic GABAA receptors (THIP and neurosteroids) have been found to induce plasticity of dopamine neurons in the ventral tegmental area (VTA). Furthermore, populations of synaptic or extrasynaptic GABAA receptor are activated, the repeated administration seems to correlate with rewarding or aversive behavioral responses, respectively. Both synaptic and extrasynaptic GABAA drugs inhibit the VTA GABAergic interneurons, thus activating the VTA DA neurons by disinhibition and this way inducing glutamatergic synaptic plasticity. However, the GABAA drugs failed to alter synaptic spine numbers. Since the GABAergic drugs are known to depress the brain metabolism and gene expression, their likely way of inducing neuroplasticity in mature neurons is by disinhibiting the principal neurons, which remains to be tested.

Key words: GABAA receptor, benzodiazepines, dendritic spines, dopamine neurons, neuroadaptation, neurosteroids

郑立卿 . 作用于GABAA受体的药物与神经可塑性[J]. 神经药理学报, 2012, 2(6): 40-48.

ZHEN Li-qing. GABAA Receptor Drugs and Neuronal Plasticity[J]. Acta Neuropharmacologica, 2012, 2(6): 40-48.

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