Pituitary adenylate cyclase-activating polypeptide (PACAP) modulates dependence-induced alcohol drinking and anxiety-like behavior in male rats
Pituitary adenylate cyclase-activating polypeptide (PACAP) modulates dependence-induced alcohol drinking and anxiety-like behavior in male rats
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DOI：
10.1038/s41386-020-00904-4
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发表时间：
2020-11-16
影响因子：
7.6
通讯作者：
Cottone, Pietro
中科院分区：
文献类型：
--
作者：
Ferragud, Antonio;Velazquez-Sanchez, Clara;Cottone, Pietro
酒精使用障碍（AUD）是一种毁灭性的疾病，由大量饮酒和戒断期定义，通常导致慢性复发过程。最初，饮酒是为了其积极的强化作用，但AUD后期的特征是饮酒以减轻戒断引起的负面情绪状态。杏仁核中的大脑应激反应系统会因过量饮酒而被招募，因反复戒断而被敏化，并有助于成瘾的发展。在这项研究中，我们研究了这样一个脑应激反应系统，垂体腺苷酸环化酶激活多肽（PACAP），及其同源受体，PAC 1 R，在酒精戒断诱导的行为。在急性戒断期间，暴露于慢性间歇性乙醇蒸汽（乙醇依赖性）的大鼠显示终纹床核（BNST）中PACAP水平显著增加，BNST是扩展杏仁核内的一个脑区，与应激和戒断密切相关。在杏仁核中央核中未观察到PACAP水平的变化。将PAC 1 R拮抗剂PACAP（6-38）向BNST中进行位点特异性微量输注，可剂量依赖性地阻断乙醇依赖性大鼠的过量酒精摄入，而不影响对照、非依赖性大鼠的总体水摄入或基础乙醇摄入。BNST内PACAP（6-38）也逆转了乙醇依赖大鼠中乙醇戒断诱导的焦虑样行为，但对对照大鼠的这一测量结果没有影响。我们的研究结果表明，慢性间歇性暴露于乙醇招募的PACAP/PAC 1 R系统的BNST和这些神经适应介导的高度饮酒和焦虑样的行为在戒断过程中观察到的，这表明该系统代表了一个主要的大脑应力元素负责负强化与酒精成瘾的“黑暗面”。
Alcohol use disorder (AUD) is a devastating illness defined by periods of heavy drinking and withdrawal, often leading to a chronic relapsing course. Initially, alcohol is consumed for its positive reinforcing effects, but later stages of AUD are characterized by drinking to alleviate withdrawal-induced negative emotional states. Brain stress response systems in the extended amygdala are recruited by excessive alcohol intake, sensitized by repeated withdrawal, and contribute to the development of addiction. In this study, we investigated one such brain stress response system, pituitary adenylate cyclase-activating polypeptide (PACAP), and its cognate receptor, PAC1R, in alcohol withdrawal-induced behaviors. During acute withdrawal, rats exposed to chronic intermittent ethanol vapor (ethanol-dependent) displayed a significant increase in PACAP levels in the bed nucleus of the stria terminalis (BNST), a brain area within the extended amygdala critically involved in both stress and withdrawal. No changes in PACAP levels were observed in the central nucleus of the amygdala. Site-specific microinfusion of the PAC1R antagonist PACAP(6-38) into the BNST dose-dependently blocked excessive alcohol intake in ethanol-dependent rats without affecting water intake overall or basal ethanol intake in control, nondependent rats. Intra-BNST PACAP(6-38) also reversed ethanol withdrawal-induced anxiety-like behavior in ethanol-dependent rats, but did not affect this measure in control rats. Our findings show that chronic intermittent exposure to ethanol recruits the PACAP/PAC1R system of the BNST and that these neuroadaptations mediate the heightened alcohol drinking and anxiety-like behavior observed during withdrawal, suggesting that this system represents a major brain stress element responsible for the negative reinforcement associated with the "dark side" of alcohol addiction.