Mesolimbic DA D1/D2 Receptors and Response to Cocaine

治疗可卡因依赖最困难的方面是戒断一段时间后可卡因使用复发的倾向。可卡因依赖者通常将其复发描述为由可卡因渴望引起的，而可卡因渴望可能是由可卡因本身的“启动”剂量引发的。事实上，对实验室动物的研究表明，低剂量的可卡因可以引发可卡因寻求行为的“复发”。在啮齿类动物中，多巴胺（DA）D2受体激动剂增强可卡因对可卡因寻求行为的启动效应，而DA D1受体激动剂抑制这种效应。在该中心的当前周期中，我们用PET测量了可卡因依赖参与者和匹配对照者的D1和D2受体，并研究了PET测量与可卡因引发可卡因服用行为的脆弱性增加之间的关系。腹侧纹状体D1受体可用性低与可卡因引发的可卡因服用行为的脆弱性增加有关。这一结果与动物数据一致，表明可卡因后刺激D1受体可能对可卡因诱导的复发具有保护作用。在纹状体中，D1受体主要位于纹状体黑质或直接途径的GABA能细胞上。因此，刺激的直接途径 多巴胺通过D1受体可能对可卡因诱导的复发有益。在本申请的下一个周期中，我们计划通过测量D1受体和κ阿片受体（KOR）， 以及它们对可卡因引发的可卡因吸食行为的预测价值。人类死后数据 提示可卡因滥用与强啡肽和KOR表达的增加有关，即κ传递的上调。在直接途径中，κ刺激抑制D1介导的信号传导。因此，可卡因滥用者kappa系统的上调可能会损害直接途径中的传递。要测试的假设是，可卡因依赖的参与者将显示增加KOR的腹侧纹状体的可用性，高KOR和低D1受体的可用性将预测可卡因诱导的可卡因服用行为的脆弱性，在实验室中研究。这些研究的结果将导致增加可卡因成瘾的神经生物学知识，并确定最有可能从选择性药物干预中受益的参与者。

The most difficult aspect of treating cocaine dependence is the propensity for relapse to cocaine use after a period of abstinence. Cocaine dependent individuals often describe their relapse as being precipitated by cocaine craving which might be triggered by a "priming" dose of cocaine itself. Indeed, studies in laboratory animals have shown that low dose cocaine can trigger "relapse" in cocaine-seeking behavior. In rodents, dopamine (DA) D2 receptors agonists augment the priming effect of cocaine on cocaine-seeking behavior, while DA D1 receptors agonists inhibit this effect. In the current cycle of this Center, we measured with PET both D1 and D2 receptors in cocaine dependent participants and matched controls, and studied the relationship between PET measurements and increased vulnerability to cocaine primed cocaine-taking behavior. Low D1 receptor availability in the ventral striatum was associated with increased vulnerability to cocaine primed cocaine-taking behavior. This result was consistent with animal data suggesting that stimulation of D1 receptors following cocaine might be protective against cocaine-induced relapse. In the striatum, D1 receptors are mainly localized on GABAergic cells of the striatonigral or direct pathway. Thus, stimulation the direct pathway by DA via D1 receptors might be beneficial against cocaine-induced relapse. In the next cycle of this application, we plan to study in more detail the neurochemistry of the direct pathway in cocaine dependence, by measuring both D1 receptors and kappa opiate receptors (KOR), and their predictive value on cocaine primed cocaine-taking behavior. Human postmortem data suggest cocaine abuse is associated with increased dynorphin and KOR expression, i.e. upregulation of the kappa transmission. In the direct pathway, kappa stimulation inhibits D1 mediated signaling. Therefore the upregulation of the kappa system in cocaine abusers might impair transmission in the direct pathway. The hypotheses to be tested are that cocaine dependent participants will show increase KOR availability in the ventral striatum, and that both high KOR and low D1 receptor availability will be predictive of vulnerability to cocaine-induced cocaine-taking behavior, as studied in the laboratory. Results of these studies will lead to increased knowledge of the neurobiology of cocaine addiction and to the identification of participants most likely to benefit from selective pharmacological intervention.