Targeting dopamine D3 receptors in cocaine addiction

靶向可卡因成瘾中的多巴胺 D3 受体

• 批准号: 9926357
• 负责人: Anna Rose Childress
• 金额: $ 2.01万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926357
• 关键词: Address; Admission activity; Affect; Affective; Affinity; Aftercare; Agonist; Alleles; Amygdaloid structure; Animals; Attention; Behavioral; Brain; Cessation of life; Clinical; Clinical Trials; Cocaine; Cocaine Dependence; Cues; Data; Development; Disadvantaged; Disease; Dopamine; Dorsal; Dose; Drug usage; Epidemic; FDA approved; Functional Magnetic Resonance Imaging; Future; Genes; Globus Pallidus; Hospitals; Human; Image; Imaging Device; Individual; Inpatients; Knowledge; Laboratories; Link; Measures; Morbidity - disease rate; Motivation; Nucleic Acid Regulatory Sequences; Pain; Participant; Patients; Performance; Pharmaceutical Preparations; Pharmacogenetics; Phase; Placebos; Prefrontal Cortex; Public Health; Pump; Randomized; Relapse; Rewards; Risk Factors; Risk-Taking; Savings; Source; Speed; System; Testing; Translations; Ventral Striatum; addiction; behavior measurement; behavioral response; clinical efficacy; cocaine use; cost; design; dopamine D3 receptor; dopamine transporter; drug reward; efficacy trial; endophenotype; experience; genetic variant; improved; innovation; mortality; neurobehavioral; neuroimaging; neurotransmission; novel; placebo group; pre-clinical; public health relevance; receptor; recruit; relapse patients; response; tool

 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.

 描述（由申请人提供）：经过三十年的全国可卡因流行以及许多临床试验，FDA 还没有批准任何药物来治疗这种痛苦且昂贵的成瘾。复发率仍然居高不下，治疗后 6 个月可达 80%。从优雅的临床前（动物）研究到临床效益的转化不佳可能部分是由于在启动大规模临床试验之前，对候选药物参与人类复发相关大脑目标的能力了解有限。拟议的项目将利用神经成像 (fMRI) 工具，结合假设驱动的神经行为探针，解决这一关键的知识差距，以确定 BP1.4979（一种专门针对多巴胺 D3 受体的新候选药物）是否可以影响与复发相关的内表型（例如，提示触发的动机回路激活；激活 抑制电路）的剂量正在考虑用于未来的临床疗效试验。 D3 受体作为成瘾靶标具有很强的前景，但安全的 D3 特异性药物非常罕见。 72 名符合影像学检查的可卡因住院患者将被随机分配接受 DA D3 部分激动剂 BP1.4979（30 毫克）或安慰剂。在药物或安慰剂诱导之前和之后，参与者将使用我们的假设驱动（大脑，具体目标 1 和行为，具体目标 2）探针进行奖励（“GO！”）和抑制（“STOP”）测试。最重要的假设是，DA D3 调节药物会减弱大脑对与奖励相关的“GO！”的行为反应。探针，同时有可能改善大脑对“停止”探针的行为反应。我们的设计还提供了自然的机会来探索（探索性目标）大脑行为测量的药物反应是否与影响（直接或间接）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、创新的探针和新颖的（以前不可用的）D3 药物是该提案的优势。