Regulation of cocaine-reinstated drug-seeking behavior by kappa-opioid receptors in the ventral tegmental area of rats.
Regulation of cocaine-reinstated drug-seeking behavior by kappa-opioid receptors in the ventral tegmental area of rats.
复制标题
大鼠腹侧被盖区卡帕阿片受体对可卡因恢复寻药行为的调节。
DOI：
10.1007/s00213-010-1812-0
复制
发表时间：
2010
影响因子：
3.4
通讯作者：
Steketee,JefferyD
中科院分区：
文献类型：
--
作者：
Sun,Wenlin;Xue,Yueqiang;Huang,Zaifang;Steketee,JefferyD
理性戒毒是目前治疗可卡因成瘾所面临的主要挑战之一。越来越多的证据表明，谷氨酸介导的腹侧被盖区(VTA)多巴胺(DA)神经元的激活可能在可卡因诱导的复吸行为中起关键作用。VTA DA神经元的活动受多种神经递质系统的调节，包括阿片类药物、5-羟色胺、多巴胺和乙酰胆碱。最近的研究表明，激活大鼠下丘脑室旁核内的κ阿片受体(κORs)可直接抑制投射到前额叶皮质和杏仁核的DA神经元的活动。由于我们先前发现阻断前额叶背侧DA受体可抑制可卡因诱导的寻找可卡因行为的恢复，暗示VTA-PFC DA回路在这一过程中起着关键作用，因此我们验证了这样的假设，即激活VTA内的κOR将阻止可卡因诱导的大鼠寻找可卡因的恢复。结果VTAκOR激动剂U50488(0~5.6gμg/侧)可剂量依赖性地抑制可卡因诱导的行为恢复。这种影响既不能用操作行为的中断来解释，也不能用药物扩散到VTA周围的区域来解释。结论表达功能性κOR的VTA DA神经元参与了可卡因诱导的大鼠脑内神经元功能的恢复。
RationaleRelapse is one of the main challenges facing the current treatment of cocaine addiction. Understanding its neurobiological mechanism is a critical step toward developing effective anti-relapse therapies.ObjectivesEmerging evidence indicates that glutamate-mediated activation of dopamine (DA) neurons in the ventral tegmental area (VTA) may be critically involved in cocaine-induced relapse to drug-seeking behavior. Activity of VTA DA neurons is modulated by multiple neurotransmitter systems including opioids, serotonin, dopamine, and acetylcholine. Recent studies demonstrated that activation of κ-opioid receptors (κORs) in the rat VTA directly inhibits the activity of a subpopulation of DA neurons projecting to the prefrontal cortex (PFC) and amygdala. Because we previously showed that blockade of DA receptors in the dorsal PFC inhibits cocaine-induced reinstatement of extinguished cocaine-seeking behavior suggesting a critical role of the VTA–PFC DA circuit in this process, we tested the hypothesis that activation of κORs in the VTA will block cocaine-induced reinstatement in rats.MethodsRats were trained to self-administer intravenous cocaine (0.125 mg/infusion) under a modified fixed-ratio five schedule. After extinction of the learned behavior, the effects of activation of VTA κORs on cocaine-induced reinstatement were studied.ResultsThe κOR agonist U50 488 (0–5.6 μg/side) microinjected into the VTA dose-dependently decreased cocaine-induced reinstatement. The effects could not be explained by either a disruption of operant behavior or diffusion of the drug to the areas surrounding the VTA. Moreover, the effect was reversed by norbinaltorphimine.ConclusionsThe VTA DA neurons expressing functional κORs are critically involved in cocaine-induced reinstatement in rats.