Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Graduate Program in Neuroscience, Washington State University, Pullman, WA, USA.
Neuropsychopharmacology. 2013 Oct;38(11):2278-85. doi: 10.1038/npp.2013.129. Epub 2013 May 21.
The kappa-opioid receptor (KOR) is the primary target for the endogenous opioid peptide dynorphin (DYN), and KORs reside within brain circuitry underlying the complex integration of information related to different behavioral domains such as motivation, negative affect, and decision-making. Alterations in extended amygdala DYNs and KOR function following chronic alcohol exposure have been shown to mediate escalated alcohol self-administration during acute withdrawal. In addition to excessive alcohol consumption and increased negative affect, other symptoms of alcohol dependence include compromised impulse control. Given that DYN and KOR expressions are dysregulated within prefrontal brain circuitry associated with decision-making and impulse control in alcohol-dependent humans and rodents, and have been shown to modify multiple neurotransmitter systems associated with impulse-control disorders, we hypothesized that KOR activation could contribute to impulsive phenotypes. To test this hypothesis, separate cohorts of male Wistar rats were trained in one of the two animal models of impulsivity: delay-discounting (DD) or stop-signal reaction time (SSRT) tasks, and once stable responding was observed, received intracerebroventricular (ICV) infusions of the KOR agonist U50,488 (0-50 μg) according to a within-subject dosing regimen. The results demonstrated a dissociable effect of U50,488 on impulsive phenotypes related to intolerance to delay or response inhibition, with selective effects in the SSRT. Furthermore, the pro-impulsive effects of KOR activation were rescued by pretreatment with the KOR antagonist nor-binaltorphimine (nor-BNI). Therefore, KOR activation was shown to induce an impulsive phenotype that was nor-BNI-sensitive. Dysregulation of impulsive behavior by increased DYN/KOR activity could serve to increase vulnerability for the initiation, or perpetuate existing patterns of excessive alcohol abuse and can enhance the probability of relapse in dependent individuals. Furthermore, KOR-mediated impulsivity has implications for numerous neuropsychiatric disorders.
κ 阿片受体（KOR）是内源性阿片肽强啡肽（DYN）的主要靶点，KOR 存在于大脑回路中，这些回路是不同行为领域（如动机、消极情绪和决策）相关信息的复杂整合的基础。慢性酒精暴露后，延伸杏仁核 DYN 和 KOR 功能的改变被证明介导了急性戒断期间酒精自我给药的增加。除了过度饮酒和增加的消极情绪外，酒精依赖的其他症状还包括冲动控制受损。鉴于 DYN 和 KOR 的表达在与酒精依赖的人类和啮齿动物的决策和冲动控制相关的前额叶大脑回路中失调，并且已经显示出可以改变与冲动控制障碍相关的多种神经递质系统，我们假设 KOR 的激活可能导致冲动表型。为了检验这一假设，分别有两组雄性 Wistar 大鼠在两种冲动性动物模型之一中接受训练：延迟折扣（DD）或停止信号反应时间（SSRT）任务，一旦观察到稳定的反应，根据亚个体给药方案接受脑室内（ICV）U50,488（0-50μg）的 KOR 激动剂输注。结果表明，U50,488 对与延迟不耐受或反应抑制相关的冲动表型具有可分离的作用，对 SSRT 具有选择性作用。此外，KOR 激活的促冲动作用可通过预先用 KOR 拮抗剂 nor-binaltorphimine（nor-BNI）预处理来挽救。因此，KOR 激活被证明会诱导出一种 nor-BNI 敏感的冲动表型。增加的 DYN/KOR 活性引起的冲动行为失调可能会增加开始或延续过度饮酒的易感性，并增加依赖个体的复发概率。此外，KOR 介导的冲动性与许多神经精神障碍有关。
