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Dopamine D3 Receptors as a Potential Therapeutic Target for Heroin Abuse

多巴胺 D3 受体作为海洛因滥用的潜在治疗靶点

基本信息

批准号：
10220928
负责人：
Brianna Elyse George
金额：
$ 4.34万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-08 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220928
关键词：
Acute Agonist Alcohols Animals Attention Automobile Driving Autoreceptors Behavior Behavioral Biological Assay Brain Centers for Disease Control and Prevention (U.S.)Chronic Clinical Cocaine Cues Data Data Analyses Development Dopamine Dopamine Receptor Drug Modelings Emotional Exposure to Extinction (Psychology)Female Future Goals Heroin Heroin Abuse Heroin Dependence Hour Hyperactivity Infusion procedures Injections Intake Literature Manuscripts Measurement Methadone Modeling Molecular Morphine Motivation Nicotine Nucleus Accumbens Opiate Addiction Opioid Opioid replacement therapy Overdose Pharmaceutical Preparations Pharmacotherapy Play Proteins Rattus Relapse Reporting Rewards Rodent Rodent Model Role Self Administration Slice Stress Therapeutic Therapeutic Uses Time Training Translations Treatment Efficacy Treatment Protocols United States Ventilatory Depression Western Blotting Withdrawal Work addiction career development dopamine D3 receptor dopamine system drug of abuse drug reinforcement drug seeking behavior effective therapy heroin use insight male mesolimbic system neurochemistry non-opioid analgesic novel opioid epidemic opioid use disorder osmotic minipump overexpression pre-clinical presynaptic receptor receptor function response side effect therapeutic target

项目摘要

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.

项目总结