The Scripps Research Institute, Department of Neuroscience, La Jolla, CA 92037, USA.
The Scripps Research Institute, Department of Neuroscience, La Jolla, CA 92037, USA.
Neuropharmacology. 2017 Oct;125:197-206. doi: 10.1016/j.neuropharm.2017.07.017. Epub 2017 Jul 19.
The central amygdala (CeA) GABAergic system is hypothesized to drive the development of alcohol dependence, due to its pivotal roles in the reinforcing actions of alcohol and the expression of negative emotion, anxiety and stress. Recent work has also identified an important role for the CeA corticotropin-releasing factor (CRF) system in the interaction between anxiety/stress and alcohol dependence. We have previously shown that acute alcohol and CRF each increase action potential-independent GABA release in the CeA via their actions at presynaptic CRF type 1 receptors (CRFs); however, the shared mechanism employed by these two compounds requires further investigation. Here we report that acute alcohol interacts with the CRF/CRF system, such that CRF and alcohol act via presynaptic CRFs and P/Q-type voltage-gated calcium channels to promote vesicular GABA release and that both compounds occlude the effects of each other at these synapses. Chronic alcohol exposure does not alter P/Q-type voltage-gated calcium channel membrane abundance or this CRF/P/Q-type voltage-gated calcium channel mechanism of acute alcohol-induced GABA release, indicating that alcohol engages this molecular mechanism at CeA GABAergic synapses throughout the transition to dependence. Thus, P/Q-type voltage-gated calcium channels, like CRFs, are key regulators of the effects of alcohol on GABAergic signaling in the CeA.
中央杏仁核（CeA）GABA 能系统被假设为驱动酒精依赖的发展，由于其在酒精的强化作用和表达负性情绪、焦虑和压力中的关键作用。最近的工作还确定了 CeA 促肾上腺皮质释放因子（CRF）系统在焦虑/压力与酒精依赖之间相互作用中的重要作用。我们之前已经表明，急性酒精和 CRF 各自通过作用于突触前 CRF 型 1 受体（CRFs）来增加 CeA 中动作电位非依赖性 GABA 释放；然而，这两种化合物所采用的共同机制需要进一步研究。在这里，我们报告说急性酒精与 CRF/CRF 系统相互作用，使得 CRF 和酒精通过突触前 CRFs 和 P/Q 型电压门控钙通道起作用，以促进囊泡 GABA 释放，并且这两种化合物在这些突触处相互阻断彼此的作用。慢性酒精暴露不会改变 P/Q 型电压门控钙通道膜丰度或这种 CRF/P/Q 型电压门控钙通道的急性酒精诱导 GABA 释放机制，表明酒精在 CeA GABA 能突触处通过这种分子机制参与整个依赖过渡。因此，像 CRFs 一样，P/Q 型电压门控钙通道是酒精对 CeA 中 GABA 能信号作用的关键调节剂。
