Mesolimbic DA D1/D2 Receptors and Response to Cocaine

中脑边缘 DA D1/D2 受体和对可卡因的反应

• 批准号: 7628365
• 负责人: MARC A LARUELLE
• 金额: $ 39.76万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628365
• 关键词: Abstinence; Accounting; Agonist; Animal Model; Autopsy; Behavior; Cells; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Controlled Study; Corpus striatum structure; Data; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dose; Dynorphins; Event; Family; Funding; Goals; Human; Impairment; Individual; Intervention; Knowledge; Laboratories; Laboratory Animals; Lead; Ligands; Localized; Measurement; Measures; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Neurobiology; Nucleus Accumbens; Opiates; Opioid Receptor; Output; Participant; Pathway interactions; Positron-Emission Tomography; Predictive Value; Probability; Progress Reports; Relapse; Research Personnel; Rodent; Self Administration; Self-Administered; Signal Transduction; Stimulus; System; Testing; Tracer; Up-Regulation; Ventral Striatum; animal data; base; cohort; craving; dopamine system; in vivo; kappa opioid receptors; neurochemistry; preclinical study; prevent; programs; radiotracer; receptor; receptor density; receptor expression; reinforcer; response; transmission process; volunteer

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.

治疗可卡因依赖性的最困难的方面是在禁欲后倾向于复发可卡因。可卡因依赖性个体通常将其复发描述为可卡因渴望引起的，这可能是由可卡因本身的“启动”剂量触发的。实际上，实验动物的研究表明，低剂量可卡因可以触发可卡因寻求可卡因行为的“复发”。在啮齿动物中，多巴胺（DA）D2受体激动剂增强了可卡因对可卡因寻求可卡因行为的启动作用，而DA D1受体激动剂抑制了这种影响。在该中心的当前周期中，我们用PET D1和D2受体在可卡因依赖的参与者和匹配的对照中进行了测量，并研究了PET测量和增加可卡因的可卡因促进可卡因行为之间的关系。腹侧纹状体中的低D1受体可利用性与可卡因发作行为的脆弱性增加有关。该结果与动物数据一致，表明可卡因后的D1受体刺激可能具有可卡因诱导的复发的保护作用。在纹状体中，D1受体主要位于纹状体或直接途径的GABA能细胞上。因此，刺激直接途径 DA通过D1受体可能对可卡因诱导的复发有益。在本应用的下一个周期中，我们计划通过测量D1受体和Kappa鸦片受体（KOR），，更详细地研究可卡因依赖性直接途径的神经化学。 以及它们对可卡因的预测价值。人类验尸数据 表明可卡因滥用与增强的驱虫和kor表达相关，即kappa传播的上调。在直接途径中，KAPPA刺激抑制D1介导的信号传导。因此，可卡因施虐者中Kappa系统的上调可能会损害直接途径中的传播。要测试的假设是可卡因依赖性参与者将显示腹侧纹状体中的KOR可用性增加，并且在实验室研究的高可卡因和低D1受体的可用性都将预测可卡因诱导的可卡因造成可卡因造成的行为。这些研究的结果将导致人们对可卡因成瘾的神经生物学的了解以及最有可能受益于选择性药理干预的参与者的识别。