伏隔核内局部GABAA受体介导的多巴胺释放的抑制。,ACS Chemical Neuroscience

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伏隔核内局部GABAA受体介导的多巴胺释放的抑制。
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-10-10 , DOI: 10.1021/acschemneuro.8b00268
Zachary D Brodnik ₁ , Aashita Batra ₁ , Erik B Oleson ₂ , Rodrigo A España ₁

Affiliation

苯二氮卓类药物构成一类精神活性药物，它们起抑制性GABAA受体的变构共激活剂的作用。这些药物可用于治疗多种精神疾病，但也具有相当大的滥用责任。尽管苯二氮卓类药物普遍使用和误用，但这些药物发挥增强作用的机制仍不完全清楚。据信，多巴胺水平的瞬时阶段性增加在确定滥用药物的增强特性方面起着重要作用，我们最近证明，全身性施用苯二氮卓类药物可增加这些事件的发生率，但同时也会降低其发生的幅度。该观察结果提供了对苯二氮卓类药物对多巴胺信号传导的药理作用的洞察力，但是，苯二氮卓类药物驱动多巴胺信号相位变化的过程仍不清楚。在这些研究中，我们研究了苯并二氮杂卓可能通过减少多巴胺的瞬时振幅的机制。我们使用快速扫描循环伏安法测试了苯二氮卓地西m和GABAA激动剂麝香酚对伏隔核脑切片诱发的多巴胺释放的影响。我们发现地西epa和麝香酚都可以降低多巴胺的释放，而通过联合应用GABAB受体拮抗剂可以阻止GABAA受体激活后多巴胺释放的减少。这些结果表明伏隔核中GABA A受体的激活通过局部GABA信号的抑制和随后的GABA B受体的激活而降低了多巴胺的释放。全面的，

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Local GABAA Receptor-Mediated Suppression of Dopamine Release within the Nucleus Accumbens.

Benzodiazepines make up a class of psychoactive drugs that act as allosteric co-activators of the inhibitory GABAA receptor. These drugs are useful for the treatment of several psychiatric disorders but also hold considerable abuse liability. Despite the common use and misuse of benzodiazepines, the mechanisms through which these drugs exert their reinforcing effects remain incompletely understood. Transient phasic increases in dopamine levels are believed to play an important role in defining the reinforcing properties of drugs of abuse, and we recently demonstrated that systemic administration of benzodiazepines increased the frequency of these events but concomitantly reduced their amplitude. This observation provides insight into the pharmacological effects of benzodiazepines on dopamine signaling, but the processes through which benzodiazepines drive changes in phasic dopamine signals remain unclear. In these studies, we investigated the mechanisms through which benzodiazepines may reduce the phasic dopamine transient amplitude. We tested the effect of the benzodiazepine diazepam and the GABAA agonist muscimol on evoked dopamine release from nucleus accumbens brain slices using fast scan cyclic voltammetry. We found that both diazepam and muscimol reduce dopamine release and that reductions in dopamine release following GABAA receptor activation can be blocked by co-application of a GABAB receptor antagonist. These results suggest that activation of GABAA receptors in the nucleus accumbens decreases dopamine release by disinhibition of local GABA signaling and subsequent activation of GABAB receptors. Overall, this work provides a putative mechanism through which benzodiazepines reduce the amplitude of phasic dopamine release in vivo.

更新日期：2018-09-25

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