Neural Mechanism of Drug-Seeking Behavior

描述（由申请人提供）：可卡因依赖是一种慢性疾病，因为即使在长时间的戒断后，复发率也很高。因此，成功的治疗必须包括预防复发。这项资助的目的是阐明取样可卡因或暴露于可卡因相关线索（例如，随身物品、可卡因吸食环境等）所产生的激励动机效应的神经机制，这两者都被认为在可卡因渴望和复发中起主要作用。可卡因和可卡因线索的激励效应涉及多巴胺（DA）、血清素（5-HT）和谷氨酸系统。此外，越来越多的证据表明，可卡因和可卡因线索激活的是不同的、但重叠的神经回路，人们非常关注DA和谷氨酸在这些回路中的作用。相比之下，很少有研究考察5-羟色胺在这些回路中的作用。最近的研究表明，5-HT2C受体（Rs）的刺激抑制了中边缘DA神经元，降低了可卡因和线索的激励效应，而5-HT2ARs的刺激可能促进这些刺激的激励效应。拟议的研究将检查有关这些影响的解剖位点的具体假设。具体来说，我们假设杏仁核中5-HT2CRs的刺激增加会抑制可卡因线索的激励动机效应，而腹侧被盖区的这些受体的刺激会抑制线索和可卡因本身的激励动机效应。此外，我们假设刺激内侧前额叶皮层的5-HT2CRs会抑制这些刺激的激励效应，而刺激该区域的5-HT2ARs则会促进这些效应。这些假设将通过检查局部输注5-羟色胺药物对在可卡因启动注射或暴露于可卡因线索后恢复已消失的可卡因寻求行为（即，在没有可卡因强化的情况下的操作性反应）的影响来检验。根据对预测效果的支持，随后的实验将检查效果的解剖学和药理学特异性。本研究将有助于阐明5-羟色胺在可卡因和可卡因线索刺激作用下的神经回路中的作用。了解这些回路可能对开发可卡因依赖的治疗方法具有重要意义。

DESCRIPTION (provided by applicant): Cocaine dependence is a chronic condition because of the high incidence of relapse that occurs even after prolonged periods of abstinence. Thus, successful treatment must include relapse prevention. The objective of this grant is to elucidate the neural mechanisms underlying incentive motivational effects produced by sampling cocaine or by exposure to cocaine-associated cues (e.g., paraphernalia, cocaine- taking environment, etc), both of which are thought to play a major role in cocaine craving and relapse. Incentive motivational effects of cocaine and cocaine cues involve dopamine (DA), serotonin (5-HT), and glutamate systems. Furthermore, there is mounting evidence that suggests cocaine and cocaine cues activate different, but overlapping neural circuits and much attention has been given to understanding the role of DA and glutamate within these circuits. In contrast, little research has examined the role of 5-HT in these circuits. Recent research suggests that stimulation of 5-HT2C receptors (Rs) inhibits mesolimbic DA neurons and decreases the incentive motivational effects of both cocaine and cues, whereas stimulation of 5-HT2ARs may facilitate incentive motivational effects of these stimuli. The proposed research will examine specific hypotheses regarding the anatomical locus of these effects. Specifically, we hypothesize that increased stimulation of 5-HT2CRs in the amygdala inhibits incentive motivational effects of cocaine cues, whereas stimulation of these receptors in the ventral tegmental area inhibits incentive motivational effects of both cues and cocaine itself. Furthermore, we hypothesize that stimulation of 5-HT2CRs in the medial prefrontal cortex inhibits the incentive motivational effects of these stimuli, whereas stimulation of 5-HT2ARs in this region facilitates the effects. The hypotheses will be tested by examining the effects of localized infusions of 5-HT drugs on reinstatement of extinguished cocaine-seeking behavior (i.e., operant responding in the absence of cocaine reinforcement) following cocaine priming injections or exposure to cocaine cues. Contingent upon support for predicted effects, subsequent experiments will examine the anatomical and pharmacological specificity of the effects. This research will help to elucidate the role of 5-HT in the neural circuits underlying incentive motivational effects of cocaine and cocaine cues. Understanding these circuits will likely have important implications for developing treatments for cocaine dependence.