A little night(PA)CAP: pituitary adenylate cyclase-activating polypeptide mediates behavioral effects of alcohol withdrawal.
A little night(PA)CAP: pituitary adenylate cyclase-activating polypeptide mediates behavioral effects of alcohol withdrawal.
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小夜（PA）CAP：垂体腺苷酸环化酶激活多肽介导酒精戒断的行为效应。
DOI：
10.1038/s41386-020-00922-2
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Barson,JessicaR
中科院分区：
文献类型：
--
作者：
Pirino,BreanneE;Barson,JessicaR
酒精使用障碍是一种慢性、复发性障碍，其特征是强迫性地寻求和摄入酒精，对饮酒失去控制的感觉，以及在戒酒期间出现的负面情感状态。对于依赖，饮酒被认为是由负强化而不是正强化驱动的，因此酒精的摄入消除了与戒断相关的厌恶状态。依赖性的出现被认为是通过大脑奖励系统的功能丧失和延伸杏仁核的应激系统的补充而发生的，延伸杏仁核包括终纹床核（BNST）、杏仁核中央核和伏隔核壳[1]。重要的是，很少有药物能有效治疗酒精使用障碍。因此，确定新的药物治疗靶点是当务之急。垂体腺苷酸环化酶激活多肽（PACAP）及其同源受体（PAC1R）参与了乙醇摄入和应激反应，它们在BNST中大量表达[2,3]。在大鼠中，慢性间歇性乙醇饮用增加了丘脑[4]室旁核细胞中PACAP的肽水平。慢性可变应激可上调BNST[5]中PACAP和PAC1R的基因表达，而在BNST中注射PACAP或PAC1R激动剂可刺激焦虑样行为。虽然这将PACAP与乙醇饮用和应激反应联系起来，但PACAP在乙醇依赖中的具体作用，以及这种作用是否通过扩展的杏仁核发生，尚不清楚。在这一期的《神经精神药理学》中，Ferragud等人验证了一个假设，即BNST的PACAP/PAC1R系统是脑应激系统的一个主要组成部分，该系统促进了乙醇依赖中出现的乙醇饮酒增加和焦虑样行为。通过对成年雄性Wistar大鼠进行8周的间歇乙醇蒸汽或空气暴露（诱导乙醇依赖的过程），作者首先使用免疫组织化学方法确定急性戒断期间（蒸汽抵消后8-10小时）扩展杏仁核中PACAP系统的变化。接下来，为了确定他们观察到的BNST中内源性PACAP水平增加对乙醇摄入和焦虑样行为的影响，他们训练第二组大鼠在急性戒断期间，在酒精蒸汽或空气暴露之前和之后的整个过程中，自我管理乙醇和水。然后，他们在急性戒断期间，在双侧注射PAC1R拮抗剂PACAP（6-38）后，对这些大鼠进行乙醇和水的自我给药测试，一周后在光-暗冲突测试中测试焦虑样行为。
Alcohol use disorder is a chronic, relapsing disorder characterized by compulsive seeking and intake of alcohol, feelings of loss of control over its consumption, and the emergence of negative affective states during abstinence [1]. With dependence, alcohol drinking is thought to be driven by negative rather than positive reinforcement, whereby the intake of alcohol removes aversive abstinence-related states. The emergence of dependence is thought to occur through a loss of function in the reward systems of the brain and a recruitment of the stress systems in the extended amygdala, which is comprised of the bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala, and nucleus accumbens shell [1]. Importantly, few medications effectively treat alcohol use disorder. Thus, identifying new pharmacotherapeutic targets is a top priority. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), and its cognate receptor (PAC1R), are involved in both ethanol intake and the stress response, and they are heavily expressed in the BNST [2, 3]. In rats, chronic intermittent access ethanol drinking increases peptide levels of PACAP in cells of the paraventricular nucleus of the thalamus [4]. Chronic variable stress upregulates gene expression of PACAP and PAC1R in the BNST [5], and injection of PACAP or a PAC1R agonist into the BNST stimulates anxiety-like behaviors, as measured in elevated plus maze and open field tests [6]. While this connects PACAP with ethanol drinking and the stress response, a specific role for PACAP in ethanol dependence, and whether or not this occurs through actions in the extended amygdala, remained unknown.In this issue of Neuropsychopharmacology, Ferragud et al.[7] tested the hypothesis that the PACAP/PAC1R system of the BNST represents a major component of the brain stress system that promotes the increased ethanol drinking and anxiety-like behavior that occur in ethanol dependence. Using 8 weeks of intermittent ethanol vapor or air exposure in adult, male Wistar rats, a procedure that induces ethanol dependence, the authors first use immunohistochemistry to identify changes in the PACAP system in the extended amygdala during acute withdrawal (8-10 h after vapor offset). Next, to determine the effects of their observed increase in endogenous PACAP levels in the BNST on ethanol intake and anxiety-like behavior, they train a second group of rats to self-administer ethanol and water prior to and then throughout the period of ethanol vapor or air exposure, during acute withdrawal. They then test these rats for ethanol and water self-administration and, one week later, for anxiety-like behavior in a light-dark conflict test, following bilateral injection into the BNST of the PAC1R antagonist, PACAP (6-38), during acute withdrawal.