Lloyd K G, Perrault G, Zivkovic B
J Pharmacol. 1985;16 Suppl 2:5-27.
The use of a multidisciplinary approach--laboratory and clinical pharmacology and experimental and human neurochemistry--has demonstrated that GABA neurons and receptors play a variety of functional roles in the mammalian brain. The present synopsis has been limited to some of the newer aspects of GABA neuron function. Thus there is strong evidence that GABA neurons are involved in the control of cerebral excitability (cf. tables I, II) and in the genesis of at least some seizures states, including certain types of human epilepsy (table III). Furthermore GABA receptor activation can be used to control seizures of diverse etiology and at least one GABA agonist, progabide, is effective in human epilepsy. There is a foundation for the belief that GABA neurons function in the control of affect and emotion. The most convincing evidence is from laboratory and clinical pharmacology studies in depression and models for the development of new antidepressant drugs. GABA agonists act as antidepressants not only in animal models such as learned helplessness, olfactory bulbectomy and the sleep-cycle but also demonstrate an antidepressant action in man. Additionally, the recent studies showing that chronic treatment by antidepressants, induce an increase in 3H-GABA "B" binding strongly support a GABAergic contribution in the mechanism of antidepressant drugs (cf. table IV). There is also some evidence for the hypothesis that GABA neurons and receptors participate in the biology of anxiety, or at least the mechanism of action of anxiolytics. This is based mainly on the known molecular pharmacology of the benzodiazepine receptor and the evidence in animal models for anxiety (table V). However in clinical trials the GABA agonist progabide is only a weak anxiolytic. A major function of GABA neurons and receptors is the regulation of the nigro-striatal dopamine pathway (table VI) and the expression of dopamine receptor mediated events (table VII). This modulation probably occurs via at least 3 mechanisms: a tonic inhibition of dopamine neuron activity regulating dopamine synthesis, turnover and release; a long term modulation controlling striatal dopamine receptor numbers, modification of the expression of dopaminergic transmission distal to the dopaminergic synapse.
采用多学科方法——实验室与临床药理学以及实验与人体神经化学——已证明γ-氨基丁酸（GABA）神经元及受体在哺乳动物大脑中发挥着多种功能作用。本综述仅限于GABA神经元功能的一些较新的方面。因此，有强有力的证据表明，GABA神经元参与大脑兴奋性的控制（参见表I、II）以及至少某些癫痫发作状态的发生，包括某些类型的人类癫痫（表III）。此外，GABA受体激活可用于控制多种病因引起的癫痫发作，并且至少有一种GABA激动剂，即普罗加比，对人类癫痫有效。有理由相信GABA神经元在情感和情绪控制中发挥作用。最有说服力的证据来自抑郁症的实验室和临床药理学研究以及新型抗抑郁药物研发模型。GABA激动剂不仅在诸如习得性无助、嗅球切除和睡眠周期等动物模型中表现出抗抑郁作用，而且在人类中也显示出抗抑郁作用。此外，最近的研究表明，抗抑郁药的长期治疗会导致3H-GABA “B” 结合增加，这有力地支持了GABA能在抗抑郁药物作用机制中的贡献（参见表IV）。也有一些证据支持这样的假说，即GABA神经元和受体参与焦虑生物学过程，或者至少参与抗焦虑药的作用机制。这主要基于苯二氮䓬受体已知的分子药理学以及焦虑动物模型中的证据（表V）。然而，在临床试验中，GABA激动剂普罗加比只是一种弱效抗焦虑药。GABA神经元和受体的一个主要功能是调节黑质-纹状体多巴胺通路（表VI）以及多巴胺受体介导事件的表达（表VII）。这种调节可能至少通过三种机制发生：对多巴胺神经元活动的紧张性抑制，调节多巴胺的合成、周转和释放；长期调节，控制纹状体多巴胺受体数量，改变多巴胺能突触远端多巴胺能传递的表达。
