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: 9249538
• 负责人: Anna Rose Childress
• 金额: $ 63.09万
• 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 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249538
• 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; Eligibility Determination; Epidemic; FDA approved; Functional Magnetic Resonance Imaging; Future; Genes; Globus Pallidus; Hospitals; Human; Image; 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; Recruitment Activity; 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; pre-clinical; public health relevance; receptor; 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.