Dopamine D3 Receptors as a Potential Therapeutic Target for Heroin Abuse

项目摘要 阿片类药物在美国的流行达到了前所未有的水平，阿片类药物的新治疗方法 和海洛因成瘾都是迫切需要的海洛因滥用传统上是用阿片类药物替代治疗的 比如美沙酮然而，这些药物具有负面副作用，例如滥用倾向， 呼吸抑制，表明需要新型，安全的药物治疗阿片类药物 使用障碍。最近有证据表明，海洛因至少部分地产生了奖励和成瘾作用。 通过激活中脑边缘多巴胺系统，海洛因寻求和摄入在临床前 成瘾模型可以通过靶向多巴胺受体的治疗来调节。多巴胺D3 受体受到了相当大的关注，因为研究表明D3受体拮抗剂可以减少线索， 诱发复吸，一种尼古丁、酒精、可卡因和阿片类药物的复发样行为模型。这些 研究结果表明，D3受体可能是药物治疗海洛因滥用的潜在靶点， D3受体拮抗剂可以降低复发的脆弱性。因此，本研究旨在研究（1）如果 D3受体特异性拮抗剂的急性和/或慢性给药可减少线索诱导的海洛因 在雄性和雌性大鼠中的恢复和（2）如果在慢性暴露于海洛因后D3受体改变和/或 灭绝是导致复发的原因因为之前的研究表明D3受体拮抗剂 急性给药后是否具有治疗效果，在具体目标1中，我们将确定慢性给药后是否具有治疗效果。 D3拮抗剂的给药比急性给药更有效， 在D3受体拮抗剂给药后显示恢复反应降低。我们的初步 数据表明，在慢性海洛因暴露后，中脑核中的D3自身受体过度活跃。 因此，在特定目标2中，我们将确定D3受体活性的这种增加是否在整个过程中保持不变。 如果女性表现出相同的变化。总的来说，拟议的研究将深入了解 D3受体拮抗剂降低复发脆弱性的潜力，以及检查D3受体拮抗剂的潜力， 受体靶点用于未来的药物开发。此外，拟议的研究将提供培训， 在行为和神经化学测定以及数据分析，解释和传播，通过 手稿和演示文稿，这将作为申请人的职业发展机会。

PROJECT SUMMARY The opioid epidemic in the United States has reached unprecedented levels, and new treatments for opioid and heroin addiction are desperately needed. Heroin abuse is traditionally treated with opioid replacement therapies like methadone. However, these medications have negative side effects such as abuse liability and respiratory depression, suggesting the need for novel, safe pharmacotherapeutic medications to treat opioid use disorder. There is recent evidence that heroin produces its rewarding and addictive effects at least partially through activation of the mesolimbic dopamine system, and that heroin seeking and intake in preclinical addiction models can be modulated by treatments that target dopamine receptors. Specifically, dopamine D3 receptors have received considerable attention, as studies have shown D3 receptor antagonists reduce cue- induced reinstatement, a model of relapse-like behavior, for nicotine, alcohol, cocaine, and opioids. These findings suggest that D3 receptors may be a potential target for pharmacotherapies to treat heroin abuse and that D3 receptor antagonists may decrease relapse vulnerability. Therefore, this study aims to investigate (1) if acute and/or chronic administration of D3 receptor specific antagonists can decrease cue-induced heroin reinstatement in male and female rats and (2) if D3 receptor alterations after chronic exposure to heroin and/or extinction are driving relapse vulnerability. Because previous studies have shown that D3 receptor antagonists have therapeutic efficacy after acute administration, in Specific Aim 1 we will determine if chronic administration of a D3 antagonist is more effective than acute administration and if male and female rats demonstrate decreased reinstatement responding after D3 receptor antagonist administration. Our preliminary data suggest that D3 autoreceptors in the nucleus accumbens are overactive after chronic heroin exposure. Therefore, in Specific Aim 2, we will determine if this increase in D3 receptor activity is maintained throughout extinction and if females show the same alterations. Collectively, the proposed studies will provide insight into the potential for D3 receptor antagonists to decrease relapse vulnerability as well as examine a potential receptor target for future pharmacotherapeutic development. Further, the proposed studies will provide training in behavioral and neurochemical assays as well as data analysis, interpretation, and dissemination through manuscripts and presentations, which will serve as career development opportunities for the applicant.