Targeting dopamine D3 receptors in cocaine addiction

 描述（由申请人提供）：经过三十年的全国可卡因流行和许多临床试验，没有FDA批准的药物用于这种痛苦和昂贵的成瘾。复发率仍然居高不下，治疗后6个月可接近80%.从优雅的临床前（动物）研究到临床益处的转化很差，部分原因可能是在启动大规模临床试验之前，对候选药物在人类中参与复发相关脑靶点的能力了解有限。拟议的项目将解决这一关键的知识差距，使用神经成像（fMRI）工具，结合假设驱动的神经行为探针，以确定BP 1.4979，一种专门针对多巴胺D3受体的新候选药物，是否可以影响复发相关的内在表型（例如，刺激回路的线索触发激活;抑制回路的激活）。D3受体作为成瘾靶点具有很强的前景，但安全的D3特异性药物非常罕见。将72名符合成像条件的可卡因住院患者随机分配至DA D3部分激动剂BP 1.4979（30 mg）或安慰剂组。在药物或安慰剂诱导之前和之后，将使用我们的假设驱动（大脑，特定目标1和行为，特定目标2）探针对参与者进行测试以获得奖励（“GO！“）和抑制（“STOP”）。过度假设是，DA D3调节药物将钝化大脑行为反应，我们的奖励相关的“去！“探针，同时潜在地改善大脑对我们的“停止”探针的行为反应。我们的设计还提供了一个自然的机会，探索（探索性目的）是否对大脑行为措施的药物反应与影响（直接或间接）DA神经传递的个体遗传变异有关，以及在住院后短暂但信息丰富的“复发窗口”期间使用可卡因。一个经验丰富的团队，创新的探头和一种新的（以前不可用的）D3药物是该提案的优势。

 DESCRIPTION (provided by applicant): After three decades of a national cocaine epidemic, and many clinical trials, there are no FDA-approved medications for this painful and costly addiction. Relapse rates remain stubbornly high, and can approach 80% at 6 months post- treatment. The poor translation from elegant preclinical (animal) studies to clinical benefit may be due, in part, to limited knowledge of the candidate medications' ability to engage relapse-relevant brain targets in humans -- prior to initiating large-scale clinical trials. The proposed project will address this critical knowledge gap, using NEURO-imaging (fMRI) tools, combined with hypothesis-driven NEURO-behavioral probes, to determine whether BP1.4979, a new candidate medication specifically targeting the dopamine D3 receptor, can impact relapse-relevant endophenotypes (e.g., cue-triggered activation of motivational circuitry; activation of inhibitory circuitry) at a dose under consideration for future clinical efficacy trials. D3 receptos have strong promise as addiction targets, but safe, D3-specific agents are very rare. Seventy-two imaging- eligible cocaine inpatients will be randomized either to the DA D3 partial agonist, BP1.4979 (30 mg), or to placebo. Prior to, and following, induction onto medication or placebo, the participants will be tested with our hypothesis-driven (brain, Specific Aim 1, and behavioral, Specific Aim 2) probes for reward ("GO!") and inhibition ("STOP"). The over-arching hypothesis is that the DA D3-modulating medication will blunt the brain- behavioral response to our reward-related "GO!" probes, while potentially improving the brain-behavioral response to our "STOP" probes. Our design also offers the natural opportunity to explore (Exploratory Aim) whether the medication response on the brain-behavioral measures is related to individual genetic variants affecting (directly or indirectly) DA neurotransmission, and to cocaine use during a brief but informative "relapse window" following the inpatient stay. An experienced team, innovative probes, and a novel (previously unavailable) D3 medication are strengths of the proposal.