Abstract：
Alcohol use disorder (AUD) is a chronic relapsing disease that is deleterious at individual, familial, and societal levels. Although AUD is one of the highest preventable causes of death in the USA, therapies for the treatment of AUD are not sufficient given the heterogeneity of the disorder and the limited number of approved medications. To provide better pharmacological strategies, it is important to understand the neurological underpinnings of AUD. Evidence implicates the endogenous dynorphin (DYN)/κ-opioid receptor (KOR) system recruitment in dysphoric and negative emotional states in AUD to promote maladaptive behavioral regulation. The nucleus accumbens shell (AcbSh), mediating motivational and emotional processes that is a component of the mesolimbic dopamine system and the extended amygdala, is an important site related to alcohol\'s reinforcing actions (both positive and negative) and neuroadaptations in the AcbSh DYN/KOR system have been documented to induce maladaptive symptoms in AUD. We have previously shown that in other nodes of the extended amygdala, site-specific KOR antagonism can distinguish different symptoms of alcohol dependence and withdrawal. In the current study, we examined the role of the KOR signaling in the AcbSh of male Wistar rats in operant alcohol self-administration, measures of negative affective-like behavior, and physiological symptoms during acute alcohol withdrawal in alcohol-dependence. To induce alcohol dependence, rats were exposed to chronic intermittent ethanol vapor for 14 h/day for three months, during which stable escalation of alcohol self-administration was achieved and pharmacological AcbSh KOR antagonism ensued. The results showed that AcbSh KOR antagonism significantly reduced escalated alcohol intake and negative affective-like states but did not alter somatic symptoms of withdrawal. Understanding the relative contribution of these different drivers is important to understand and inform therapeutic efficacy approaches in alcohol dependence and further emphasis the importance of the KOR/DYN system as a target for AUD therapeutics.
摘要：
酒精使用障碍（AUD）是一种慢性复发性疾病，对个体有害，家族性,和社会水平。尽管AUD是美国最高可预防的死亡原因之一，考虑到疾病的异质性和批准的药物数量有限,用于治疗AUD的疗法还不够.为了提供更好的药理策略，重要的是要了解AUD的神经基础。证据表明，内源性强啡肽（DYN）/κ阿片受体（KOR）系统在焦虑和负性情绪状态下募集，以促进适应不良的行为调节。伏隔核壳（AcbSh），调解动机和情绪过程，是中脑边缘多巴胺系统和扩展杏仁核的组成部分，在AcbShDYN/KOR系统中，是与酒精的强化作用（阳性和阴性）和神经适应相关的重要部位，已被证明在AUD中诱发适应不良症状。我们之前已经证明，在扩展杏仁核的其他节点中，位点特异性KOR拮抗作用可以区分酒精依赖和戒断的不同症状。在目前的研究中,我们研究了KOR信号在雄性Wistar大鼠AcbSh中的作用，消极情感样行为的衡量标准，酒精依赖急性酒精戒断期间的生理症状。诱导酒精依赖，大鼠暴露于慢性间歇性乙醇蒸气14小时/天，持续三个月，在此期间实现了酒精自我给药的稳定升级,随后出现了药物AcbShKOR拮抗作用.结果表明，AcbShKOR拮抗作用显着降低了酒精摄入量的增加和负面的情感样状态，但并未改变戒断的躯体症状。了解这些不同驱动因素的相对贡献对于理解和告知酒精依赖的治疗功效方法很重要，并进一步强调KOR/DYN系统作为AUD治疗目标的重要性。
