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Dopamine D3 receptor antagonists for treating drug addiction: Preclinical models

用于治疗药物成瘾的多巴胺 D3 受体拮抗剂：临床前模型

基本信息

批准号：
10267525
负责人：
Eliot Gardner
金额：
$ 43.21万
依托单位：
NATIONAL INSTITUTE ON DRUG ABUSE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10267525
关键词：
Addictive Behavior Analgesics Animal Model Behavior Biochemical Biological Assay Biology Brain Chemicals Chronic Collaborations Cues Development Dose Drug Addiction Drug Design Electrical Stimulation of the Brain Exposure to Extinction (Psychology)Funding Goals High Pressure Liquid Chromatography Human Resources Institution Intravenous Knockout Mice Laboratories Laboratory Animals Laboratory Rat Ligands Maintenance Microdialysis Modeling Molecular Mus Naloxone National Institute of Drug Abuse Opiate Addiction Opioid Oral Oxycodone Pain management Pharmaceutical Preparations Pharmacotherapy Polymerase Chain Reaction Pre-Clinical Model Prevention Proteins Psychological reinforcement Public Health RNA Rattus Receptor Gene Reinforcement Schedule Relapse Reporting Research Reverse Transcription Rewards Role Sampling Scientist Self Administration Severities Stress Sucrose Techniques Testing United States Western Blotting Withdrawal Work addiction clinical pain conditioned place preference craving design dopamine D3 receptor in vivo interest novel opioid abuse opioid epidemic opioid use disorder pre-clinical prescription opioid prevent programs receptor response

项目摘要

During the present reporting period, modest laboratory work was conducted on this project. Working in collaboration with PIs and lab personnel from Dr. Newman's section and Dr. Xi's Addiction Biology Unit, we explored the effect of the dopamine D3 receptor (D3R) antagonist VK4-116 on oxycodone self-administration and oxycodone-triggered relapse to oxycodone-seeking behavior using the reinstatement model. We also tested the effects of VK4-116 on oxycodone's antinociceptive (i.e., analgesic) effects. Prescription opioids such as oxycodone are highly effective analgesics for clinical pain management, but their misuse and abuse have led to the current opioid epidemic in the United States. In order to ameliorate this public health crisis, the development of effective pharmacotherapies for the prevention and treatment of opioid abuse and addiction is essential and urgently required. We therefore evaluated - in laboratory rats - the potential utility of VK4-116, a novel and highly selective dopamine D3R antagonist, for the prevention and treatment of prescription opioid use disorders. Pretreatment with VK4-116 (5-25 mg/kg, i.p.) dose-dependently inhibited the acquisition and maintenance of oxycodone self-administration. VK4-116 also lowered the break-point (BP) for oxycodone self-administration under a progressive-ratio schedule of reinforcement, shifted the oxycodone dose-response curve downward, and inhibited oxycodone extinction responding and reinstatement of oxycodone-seeking behavior. In addition, VK4-116 pretreatment dose-dependently enhanced the antinociceptive effects of oxycodone and reduced naloxone-precipitated conditioned place aversion in rats chronically treated with oxycodone. In contrast, VK4-116 had little effect on oral sucrose self-administration. Taken together, these findings indicate a central role for D3Rs in opioid reward and support further development of VK4-116 as an effective agent for mitigating the development of opioid addiction, reducing the severity of withdrawal and preventing relapse.

在本报告所述期间，就这一项目进行了少量的实验室工作。我们与来自纽曼博士部门和席博士成瘾生物学单位的PI和实验室人员合作，使用恢复模型探索多巴胺D3受体（D3 R）拮抗剂VK 4 -116对羟考酮自我给药和羟考酮触发的羟考酮寻求行为复发的影响。我们还测试了VK 4 -116对羟考酮的抗伤害性（即，镇痛）作用。处方阿片类药物如羟考酮是临床疼痛管理的高效镇痛药，但其误用和滥用导致了目前美国阿片类药物的流行。为了缓解这一公共卫生危机，开发有效的药物疗法来预防和治疗阿片类药物滥用和成瘾是至关重要和迫切需要的。因此，我们在实验室大鼠中评估了VK 4 -116（一种新型高选择性多巴胺D3 R拮抗剂）用于预防和治疗处方阿片类药物使用障碍的潜在效用。用VK4-116（5-25 mg/kg，i.p.）剂量依赖性地抑制羟考酮自我给药的获得和维持。VK 4 -116还降低了在递增比例强化方案下羟考酮自我给药的断点（BP），使羟考酮剂量-反应曲线下移，并抑制羟考酮消退反应和羟考酮寻求行为的恢复。此外，VK 4 -116预处理剂量依赖性地增强了羟考酮的抗伤害效应，并减少了羟考酮长期治疗大鼠中纳洛酮诱发的条件性位置厌恶。相比之下，VK 4 -116对口服蔗糖自我给药几乎没有影响。总之，这些发现表明D3 R在阿片类药物奖赏中的核心作用，并支持进一步开发VK 4 -116作为减轻阿片类药物成瘾发展、降低戒断严重程度和预防复发的有效药物。