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通过采样可卡因或暴露于可卡因相关线索（例如，工具、吸食可卡因的环境等），这两种因素都被认为在可卡因渴望和复吸中起主要作用。可卡因和可卡因线索的激励作用涉及多巴胺（DA），5-羟色胺（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不同的，但重叠的神经回路，并给予了很多关注，以了解DA和谷氨酸在这些回路中的作用。相反，很少有研究探讨5-HT在这些回路中的作用。最近的研究表明，5-HT 2C受体（Rs）的刺激抑制中脑边缘DA神经元，并降低可卡因和线索的激励动机效应，而5-HT 2ARs的刺激可能会促进这些刺激的激励动机效应。拟议的研究将检查有关这些影响的解剖学位点的具体假设。具体来说，我们假设，增加刺激杏仁核中的5-HT 2CRs抑制可卡因线索的激励动机的影响，而这些受体在腹侧被盖区的刺激抑制两个线索和可卡因本身的激励动机的影响。此外，我们假设，5-HT 2CRs在内侧前额叶皮层的刺激抑制这些刺激的激励动机的影响，而5-HT 2ARs在这个区域的刺激促进的效果。将通过检查局部输注5-HT药物对恢复消失的可卡因寻求行为的影响来检验这些假设（即，在没有可卡因强化的情况下的操作性反应）。根据对预测效应的支持，后续实验将检查效应的解剖学和药理学特异性。这项研究将有助于阐明5-HT在可卡因和可卡因线索的激励性动机效应背后的神经回路中的作用。了解这些电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.