Dopamine D3 Receptors as a Potential Therapeutic Target for Heroin Abuse

项目总结 美国阿片类药物流行达到前所未有的水平，阿片类药物的新疗法 人们迫切需要海洛因成瘾。海洛因滥用传统上是用阿片类药物替代治疗的 像美沙酮这样的疗法。然而，这些药物有负面副作用，如滥用倾向和 呼吸抑制，表明需要新的、安全的药物治疗阿片类药物 使用无序。最近有证据表明，海洛因至少部分地产生了有益和上瘾的效果。 通过激活中脑边缘多巴胺系统，临床前海洛因的寻找和摄取 成瘾模型可以通过针对多巴胺受体的治疗来调节。具体地说，多巴胺D3 受体受到了相当大的关注，因为研究表明，D3受体拮抗剂减少了信号转导- 尼古丁、酒精、可卡因和阿片类药物的诱导恢复，一种复发行为的模型。这些 研究结果表明，D3受体可能是治疗海洛因滥用和药物滥用的潜在靶点 D3受体拮抗剂可能会降低复发的易感性。因此，本研究旨在调查(1)是否 急性和/或长期给予D3受体特异性拮抗剂可减少线索诱导的海洛因 雄性和雌性大鼠的恢复和(2)慢性海洛因和/或暴露后D3受体的变化 物种灭绝正在加剧复发的脆弱性。因为之前的研究表明D3受体拮抗剂 在急性给药后有疗效，在特定的目标1我们将确定是否慢性 给予D3拮抗剂比急性给药更有效，如果雄性和雌性大鼠 显示给予D3受体拮抗剂后恢复反应降低。我们的预赛 数据表明，慢性海洛因暴露后，伏隔核中的D3自身受体过度活跃。 因此，在特定的目标2中，我们将确定D3受体活性的这种增加是否贯穿始终 如果雌性动物表现出同样的变化。总的来说，拟议的研究将提供对 D3受体拮抗剂降低复发易感性的潜力以及检测潜在的 受体是未来药物治疗发展的靶点。此外，拟议的研究将提供培训 在行为和神经化学分析以及数据分析、解释和传播中 手稿和演示文稿，这将成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.