Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release
Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release
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DOI：
10.1016/j.neuron.2016.08.017
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发表时间：
2016-09-21
期刊：
影响因子：
16.2
通讯作者：
Conn, P. Jeffrey
中科院分区：
文献类型：
--
作者：
Foster, Daniel J.;Wilson, Jermaine M.;Conn, P. Jeffrey
毒蕈碱受体代表了精神分裂症的一个有前途的治疗靶点，但毒蕈碱调节剂抗精神病功效的机制尚不清楚。在这里，我们报告纹状体棘投射神经元上 M-4 受体的激活导致一种新形式的多巴胺能调节，导致纹状体多巴胺释放持续抑制，在去除毒蕈碱受体激动剂后 30 分钟以上观察到这一现象。此外，M-4 介导的多巴胺释放持续抑制和 M-4 激活剂的抗精神病样功效都需要通过 CB2 大麻素受体的完整信号传导。这些发现强调了一种新机制，通过该机制纹状体胆碱能和大麻素信号传导导致多巴胺能传输持续减少以及预测抗精神病药疗效的并发行为效应。
Muscarinic receptors represent a promising therapeutic target for schizophrenia, but the mechanisms underlying the antipsychotic efficacy of muscarinic modulators are not well understood. Here, we report that activation of M-4 receptors on striatal spiny projection neurons results in a novel form of dopaminergic regulation resulting in a sustained depression of striatal dopamine release that is observed more than 30 min after removal of the muscarinic receptor agonist. Furthermore, both the M-4-mediated sustained inhibition of dopamine release and the antipsychotic- like efficacy of M-4 activators were found to require intact signaling through CB2 cannabinoid receptors. These findings highlight a novel mechanism by which striatal cholinergic and cannabinoid signaling leads to sustained reductions in dopaminergic transmission and concurrent behavioral effects predictive of antipsychotic efficacy.