Understanding the role α7 nicotinic receptors play in dopamine efflux in nucleus accumbens.
Understanding the role α7 nicotinic receptors play in dopamine efflux in nucleus accumbens.
复制标题
了解 α7 烟碱受体在伏隔核多巴胺流出中的作用。
DOI：
10.1021/cn500126t
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发表时间：
2014
影响因子：
5
通讯作者：
Gutkin,Boris
中科院分区：
文献类型：
--
作者：
Maex,Reinoud;Grinevich,VladimirP;Grinevich,Valentina;Budygin,Evgeny;Bencherif,Merouane;Gutkin,Boris
α7亚型的神经元烟碱乙酰胆碱受体（NNR）已被证明有助于脑桥核中多巴胺的释放。然而，作用部位和潜在机制尚不清楚。在这里，我们采用了电路建模方法，支持电化学在体内记录，以澄清这个问题。模型揭示了选择性α7部分激动剂TC-7020引起的脑多巴胺外排下降的两种潜在机制。TC-7020可使主要位于多巴胺能神经元或多巴胺能传入神经元上的α7 NNR脱敏，或者激活位于多巴胺能传入神经元上的α7 NNR，使其激活到腹侧被盖区的GABA能中间神经元。然而，只有基于脱敏的模型才能解释共同应用的PNU-120596（一种正变构调节剂）的中和作用。根据我们的研究结果，最可能的作用部位是终末前α7 NNR，它控制皮层传入神经向延髓核释放谷氨酸。这些发现为进一步研究α7 NNR激动剂作为与中脑边缘多巴胺能张力增强相关的疾病（如精神分裂症和成瘾）的治疗提供了理论基础。
Neuronal nicotinic acetylcholine receptors (NNRs) of the α7 subtype have been shown to contribute to the release of dopamine in the nucleus accumbens. The site of action and the underlying mechanism, however, are unclear. Here we applied a circuit modeling approach, supported by electrochemical in vivo recordings, to clarify this issue. Modeling revealed two potential mechanisms for the drop in accumbal dopamine efflux evoked by the selective α7 partial agonist TC-7020. TC-7020 could desensitize α7 NNRs located predominantly on dopamine neurons or glutamatergic afferents to them or, alternatively, activate α7 NNRs located on the glutamatergic afferents to GABAergic interneurons in the ventral tegmental area. Only the model based on desensitization, however, was able to explain the neutralizing effect of coapplied PNU-120596, a positive allosteric modulator. According to our results, the most likely sites of action are the preterminal α7 NNRs controlling glutamate release from cortical afferents to the nucleus accumbens. These findings offer a rationale for the further investigation of α7 NNR agonists as therapy for diseases associated with enhanced mesolimbic dopaminergic tone, such as schizophrenia and addiction.