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：
9555585
负责人：
Eliot Gardner
金额：
$ 27.93万
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/9555585
关键词：
Addictive Behavior Affinity Alcohol consumption Animal Model Animals Attenuated Behavior Behavioral Model Biochemical Biological Assay Brain Chemicals Cocaine Cues Dose Drug Addiction Drug Design Electrical Stimulation of the Brain Exposure to Extinction (Psychology)Food deprivation (experimental)Funding Goals High Pressure Liquid Chromatography Institution Intravenous Knockout Mice Laboratories Laboratory Animals Laboratory Finding Laboratory Rat Lead Ligands Microdialysis Molecular Mus Naltrexone National Institute of Drug Abuse Oxycodone Pharmaceutical Preparations Polymerase Chain Reaction Pre-Clinical Model Proteins Psychological reinforcement Publications RNA Rattus Receptor Gene Relapse Reporting Research Reverse Transcription Rewards Role Sampling Scientist Self Administration Series Stress Techniques Testing Western Blotting Work addiction approach behavior craving design disorder later incidence prevention dopamine D3 receptor in vivo interest novel novel therapeutics phenylpiperazine pre-clinical preference programs tetrahydropalmatine

项目摘要

During the present reporting period, modest laboratory work was conducted on this project. In addition, a backlog of laboratory findings on this project were brought forward to the publication stage during this reporting period. First, using a new additional animal behavioral model, we reported that our lead proof-of-concept dopamine D3 receptor antagonist compound SB277011A decreases binge-like consumption of ethanol in C57BL/J6 mice. Second, we reported that SB277011A attenuates drug- or food-deprivation stress-induced reactivation of the expression of cocaine-induced conditioned place preference in laboratory rats. Third, we reported that SB277011A significantly accelerates extinction to environmental cues associated with cocaine-induced place preference in laboratory rats. Fourth, we reported that SB277011A does not alter Pavlovian conditioned approach behaviors in rats (sign-tracking versus goal-tracking). Fifth, we reported on a new and novel series of 4-phenylpiperazines with exceptionally high dopamine D3 receptor affinities and/or selectivities. Compound 19 of this new chemical series inhibited oxycodone-induced hyperlocomotion in mice, and inhibited oxycodone-induced locomotor sensitization. In addition, pretreatment with compound 19 dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference in laboratory rats. Sixth, we reported that a combination of levo-tetrahydropalmatine and low dose naltrexone constitutes a promising new therapy for prevention of relapse to cocaine-seeking behavior.

在本报告期间，对该项目进行了适度的实验室工作。此外，在此报告期间，对该项目的实验室调查结果进行了积压。首先，使用新的额外动物行为模型，我们报告说，我们的铅概念验证多巴胺D3受体拮抗剂化合物SB277011A可减少C57BL/J6小鼠中乙醇的暴饮暴食。其次，我们报道了SB277011A减弱可卡因诱导的可卡因诱导的调节性位置偏好在实验室大鼠中的表达的重新激活。第三，我们报告说，SB277011a显着加速了与可卡因引起的实验室大鼠相关的环境线索。第四，我们报告说SB277011A不会改变大鼠的帕夫洛夫条件方法行为（标志跟踪与目标跟踪）。第五，我们报道了一系列新的4-苯基哌嗪系列，具有异常高的多巴胺D3受体亲和力和/或选择性。该新化学系列的化合物19抑制了小鼠中羟考酮诱导的超取代性，并抑制了羟考酮诱导的运动敏化。此外，用化合物19剂量依赖性预处理抑制了羟考酮诱导的有条件的位置偏好在实验室大鼠中的获取。第六，我们报道说，Levo-Atrahydropalmatine和低剂量纳曲酮的结合构成了一种有希望的新疗法，可预防对可卡因寻求可卡因的复发。