Nicotinic and opioid receptor regulation of striatal dopamine D2-receptor mediated transmission.
Nicotinic and opioid receptor regulation of striatal dopamine D2-receptor mediated transmission.
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DOI：
10.1038/srep37834
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发表时间：
2016-11-25
影响因子：
4.6
通讯作者：
Ford CP
中科院分区：
文献类型：
--
作者：
Mamaligas AA;Cai Y;Ford CP
除了多巴胺神经元放电，胆碱能中间神经元（ChIs）通过多巴胺轴突终末上的突触前烟碱受体（nAChRs）调节纹状体中多巴胺的释放。ChIs的同步活动是通过该途径引起多巴胺释放所必需的。双突触烟碱调制的频率依赖性导致了这样的假设，即nAChR在多巴胺能微电路中充当高通滤波器。在这里，我们使用光遗传学选择性地直接刺激纹状体中的ChI或多巴胺末梢。为了测量多巴胺释放的功能后果，通过病毒过表达的钾通道（GIRK2）在中型多刺神经元（MSN）中评估D2受体突触活性。我们发现，尼古丁介导的多巴胺释放在较高的频率钝化，因为nAChRs表现出长期脱敏后，一个单一的脉冲的同步ChI活性。然而，当单独刺激多巴胺神经元时，nAChRs在任何频率下都没有影响。我们进一步评估了阿片受体如何调节这两种释放机制。κ阿片受体激动剂U69593通过两种途径降低D2受体活性，而μ阿片受体激动剂DAMGO仅通过胆碱能介导的多巴胺释放降低D2受体活性。因此，当由多巴胺神经元或胆碱能中间神经元驱动时，多巴胺的释放可以被独立地调节。
In addition to dopamine neuron firing, cholinergic interneurons (ChIs) regulate dopamine release in the striatum via presynaptic nicotinic receptors (nAChRs) on dopamine axon terminals. Synchronous activity of ChIs is necessary to evoke dopamine release through this pathway. The frequency-dependence of disynaptic nicotinic modulation has led to the hypothesis that nAChRs act as a high-pass filter in the dopaminergic microcircuit. Here, we used optogenetics to selectively stimulate either ChIs or dopamine terminals directly in the striatum. To measure the functional consequence of dopamine release, D2-receptor synaptic activity was assessed via virally overexpressed potassium channels (GIRK2) in medium spiny neurons (MSNs). We found that nicotinic-mediated dopamine release was blunted at higher frequencies because nAChRs exhibit prolonged desensitization after a single pulse of synchronous ChI activity. However, when dopamine neurons alone were stimulated, nAChRs had no effect at any frequency. We further assessed how opioid receptors modulate these two mechanisms of release. Bath application of the κ opioid receptor agonist U69593 decreased D2-receptor activation through both pathways, whereas the μ opioid receptor agonist DAMGO decreased D2-receptor activity only as a result of cholinergic-mediated dopamine release. Thus the release of dopamine can be independently modulated when driven by either dopamine neurons or cholinergic interneurons.
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影响因子：
16.2
作者：
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