Dissociable effects of kappa-opioid receptor activation on impulsive phenotypes in wistar rats.
Dissociable effects of kappa-opioid receptor activation on impulsive phenotypes in wistar rats.
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kappa-阿片受体激活对 Wistar 大鼠冲动表型的分离效应。
DOI：
10.1038/npp.2013.129
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Kissler,JessicaL
中科院分区：
文献类型：
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作者：
Walker,BrendanM;Kissler,JessicaL
κ-阿片受体（KOR）是内源性阿片肽强啡肽（DYN）的主要靶点，并且KOR驻留在脑回路中，该脑回路是与不同行为领域（例如动机、负面影响和决策）相关的信息的复杂整合的基础。长期酒精暴露后杏仁核DYN和KOR功能的改变已被证明可以介导急性戒断期间酒精自我给药的增加。除了过量饮酒和增加负面影响外，酒精依赖的其他症状包括冲动控制受损。鉴于DYN和KOR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脑回路中失调，并且已被证明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激活可能有助于冲动表型。为了验证这一假设，在两种冲动性动物模型之一中训练单独的雄性Wistar大鼠队列：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，根据受试者内给药方案接受KOR激动剂U 50，488（0-50 μg）的脑室内（ICV）输注。结果表明，U 50，488对与延迟或反应抑制不耐受相关的冲动表型具有可分离的作用，在SSRT中具有选择性作用。此外，预处理与KOR拮抗剂nor-binaltorphimine（nor-BNI）的KOR激活的前冲动的影响获救。因此，KOR激活显示诱导对nor-BNI敏感的冲动表型。DYN/KOR活性增加导致的冲动行为失调可能会增加启动的脆弱性，或使现有的过度酗酒模式永久化，并可能增加依赖性个体复发的可能性。此外，KOR介导的冲动性对许多神经精神疾病有影响。
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.