Walters Seth H, Levitan Edwin S
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA.
Schizophr Bull. 2020 Apr 10;46(3):643-649. doi: 10.1093/schbul/sbz085.
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.
许多精神科药物是弱碱，它们在突触小泡中蓄积并从中释放，但小泡药物释放的功能影响在很大程度上尚不清楚。在这里，我们用快速扫描循环伏安法研究抗焦虑抗精神病药物氰美马嗪的小泡释放对电诱发的纹状体多巴胺反应的影响。值得注意的是，在存在纳摩尔浓度的细胞外氰美马嗪的情况下，脑片中的小泡氰美马嗪释放可使多巴胺反应增加30倍。动力学分析和多次刺激实验表明，这是通过诱导可释放多巴胺池的延迟排空而发生的。同样与多巴胺释放增加一致的是，一种拮抗剂（二氢-β-刺桐碱）表明烟碱型乙酰胆碱受体参与了小泡氰美马嗪的作用，该受体可直接导致多巴胺释放。因此，氰美马嗪的小泡释放可能通过募集兴奋性胆碱能输入以诱导额外的释放阶段，从而显著增强多巴胺能突触传递。更普遍地说，这项研究表明，通过酸性捕获在小泡中蓄积后的突触药物释放可以扩展精神科药物的药效学。
