Targeting dopamine D3 receptors in cocaine addiction

 描述(由申请者提供)：经过三十年的全国可卡因流行和许多临床试验，没有FDA批准的药物来治疗这种痛苦和昂贵的成瘾。复发率仍然居高不下，治疗后6个月复发率可达80%。从优雅的临床前(动物)研究到临床益处的糟糕转换可能部分是由于在启动大规模临床试验之前，对候选药物在人类身上吸引与复发相关的大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鸿沟，使用神经成像(FMRI)工具，结合假设驱动的神经行为探针，确定专门针对多巴胺D3受体的新候选药物BP1.4979是否可以影响复发相关的内表型(例如，提示触发的激励电路激活；抑制电路的激活)，其剂量正在考虑用于未来的临床疗效试验。D3受体作为成瘾靶点的前景很好，但安全的、D3特异性的药物非常罕见。72名符合成像条件的可卡因住院患者将被随机分为DA D3部分激动剂BP1.4979(30毫克)或安慰剂。在被诱导服用药物或安慰剂之前和之后，参与者将接受我们的假设驱动的(大脑，特定目标1，和行为，特定目标2)的奖励探测器(“开始！”)测试。和抑制(“停止”)。最重要的假设是，DA D3调节药物将削弱大脑行为对我们与奖励相关的“GO！”的反应。探测，同时潜在地改善对我们的“停止”探测的大脑行为反应。我们的设计还提供了自然的机会来探索(探索性目的)大脑行为测量的药物反应是否与(直接或间接)影响DA神经传递的个体遗传变异有关，以及与住院后短暂但信息丰富的“复发窗口”期间可卡因的使用有关。经验丰富的团队、创新的探头和一种新颖的(以前无法获得的)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.