Vesicular Antipsychotic Drug Release Evokes an Extra Phase of Dopamine Transmission.
Vesicular Antipsychotic Drug Release Evokes an Extra Phase of Dopamine Transmission.
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DOI：
10.1093/schbul/sbz085
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发表时间：
2019-07
影响因子：
6.6
通讯作者：
Seth H Walters;E. Levitan
中科院分区：
文献类型：
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作者：
Seth H Walters;E. Levitan
许多精神科药物是在突触囊泡中积累和释放的弱碱，但囊泡药物释放的功能影响在很大程度上是未知的。在这里，我们用快速扫描循环伏安法研究了抗焦虑药物氰胺嗪的囊泡释放对电诱发纹状体多巴胺反应的影响。值得注意的是，在纳米摩尔胞外氰胺嘧啶存在的情况下，脑片中囊泡释放的氰胺嘧啶可使多巴胺反应增加30倍。动力学分析和多重刺激实验表明，这是通过诱导可释放多巴胺池的延迟排空发生的。与多巴胺释放增加相一致的是，一种拮抗剂（二氢-β-红血碱）与烟碱乙酰胆碱受体相关，而烟碱乙酰胆碱受体可直接引起多巴胺释放，参与水泡胞嘧啶的作用。因此，胞胺嘧啶的囊性释放可以显著增强多巴胺能突触传递，可能是通过招募兴奋性胆碱能输入来诱导额外的释放期。更一般地说，这项研究表明，酸诱捕在囊泡积累后的突触药物释放可以扩大精神药物的药效学。
Many psychiatric drugs are weak bases that accumulate in and are released from synaptic vesicles, but the functional impact of vesicular drug release is largely unknown. Here, we examine the effect of vesicular release of the anxiolytic antipsychotic drug cyamemazine on electrically evoked striatal dopamine responses with fast scan cyclic voltammetry. Remarkably, in the presence of nanomolar extracellular cyamemazine, vesicular cyamemazine release in the brain slice can increase dopamine responses 30-fold. Kinetic analysis and multiple stimulation experiments show that this occurs by inducing delayed emptying of the releasable dopamine pool. Also consistent with increased dopamine release, an antagonist (dihydro-β-erythroidine) implicates nicotinic acetylcholine receptors, which can directly cause dopamine release, in the vesicular cyamemazine effect. Therefore, vesicular release of cyamemazine can dramatically enhance dopaminergic synaptic transmission, possibly by recruiting an excitatory cholinergic input to induce an extra phase of release. More generally, this study suggests that synaptic drug release following vesicular accumulation by acidic trapping can expand psychiatric drug pharmacodynamics.