Mesolimbic DA D1/D2 Receptors and Response to Cocaine

治疗可卡因依赖的最困难的方面是在一段时间的戒断后有重新使用可卡因的倾向。可卡因依赖者经常将他们的旧病复发描述为对可卡因的渴望导致的，这种渴望可能是由可卡因本身的“启动”剂量引发的。事实上，对实验动物的研究表明，低剂量的可卡因会引发可卡因寻求行为的“复发”。在啮齿类动物中，多巴胺（DA） D2受体激动剂增强了可卡因对可卡因寻求行为的启动效应，而DA D1受体激动剂抑制了这种效应。在本中心的当前周期中，我们用PET测量了可卡因依赖参与者和匹配对照的D1和D2受体，并研究了PET测量与可卡因引发的可卡因服用行为易感性增加之间的关系。腹侧纹状体D1受体的低可用性与对可卡因引发的可卡因服用行为的易感性增加有关。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有保护作用。在纹状体中，D1受体主要定位于纹状体或直接通路的gaba能细胞上。因此，刺激的直接途径

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.