Impact of Cocaine History on Pharmacotherapy Effectiveness

可卡因史对药物治疗效果的影响

• 批准号: 10750162
• 负责人: Madison M Marcus
• 金额: $ 1.94万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-25 至 2024-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10750162
• 关键词: Animals; Attenuated; Basic Science; Behavior; Behavioral; CHRM1 gene; Choice Behavior; Clinical; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine use disorder; Complex; Data; Development; Dopamine; Drug usage; Effectiveness; Environment; Experimental Designs; Exposure to; Female; Fiber; Food; Frequencies; Health; Hour; Human; Infusion procedures; Knowledge; Laboratory Animals; Measures; Mediating; Methadone; Methods; Modeling; Monitor; Muscarinic Acetylcholine Receptor; Naltrexone; Neurobiology; Nucleus Accumbens; Opiate Addiction; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Photometry; Procedures; Psychological reinforcement; Public Health; Publications; Publishing; Rattus; Recording of previous events; Research; Rodent; Signal Transduction; Source; Substance Use Disorder; Technology; Testing; Training; United States; United States Food and Drug Administration; addiction; behavioral pharmacology; behavioral phenotyping; career development; cocaine self-administration; cocaine use; epidemiologic data; experimental study; human subject; improved; innovation; male; neural; neurochemistry; non-drug; nonhuman primate; opioid use disorder; overdose death; positive allosteric modulator; pre-clinical; pre-clinical research; reinforcer; response; reward circuitry; screening; treatment effect

PROJECT SUMMARY With cocaine-related overdose deaths increasing every year, cocaine abuse is a serious public health concern. Despite decades of basic research, there are still no Food and Drug-approved pharmacotherapies for cocaine use disorder (CUD). A growing body of evidence suggests that prior cocaine use history may alter the development and screening of new CUD pharmacotherapies. We propose to leverage the translational utility of preclinical drug-vs-nondrug choice procedures to determine how different cocaine self-administration histories impact the effectiveness of the muscarinic acetylcholine receptor (mAChR)1 positive allosteric modulator VU0364572 to attenuate cocaine-vs-food choice and cocaine-induced increases in nucleus accumbens (NAc) dopamine (DA) release using fiber photometry (i.e., dLight). The scientific premise of this project is that candidate medications that are effective in decreasing drug choice across a broader range of experimental conditions, including cocaine history, would be hypothesized to be more effective clinically. Aim 1 will determine the effects of behavioral history (i.e., short- vs extended-access cocaine self-administration) on VU0364572 effectiveness to attenuate cocaine-vs-food choice behavior. In a 2 x 4 experimental design, each group will undergo either short-access (ShA) or extended-access (EA) cocaine self-administration conditions. Under these two access conditions, effects of 4 treatments (vehicle, 0.32, 1.0, and 1.8 mg/kg VU0364572) will be assessed. Aim 2 will determine the effects of cocaine history on effectiveness of VU0364572 to attenuate cocaine-elevated NAc DA release using dLight technology. In a 3 x 2 experimental design, each group will be exposed to one of three cocaine access conditions (ShA, EA, or cocaine naïve) and either vehicle or VU0364572 treatment. Using dLight fiber photometry, NAc DA response to cocaine infusions will be assessed. These neurochemical endpoints will be compared across groups and collected in conjunction with cocaine-vs- food choice data, allowing for within-subjects comparison of neurochemical and behavioral data. Completion of these studies will test innovative and translationally relevant hypotheses regarding the effects of cocaine history on mAChR1 PAM efficacy to decrease cocaine self-administration and cocaine-induced enhancement of mesolimbic DA signaling.

项目概要 随着与可卡因过量相关的死亡人数逐年增加，可卡因滥用已成为一个严重的公共卫生问题。 尽管进行了数十年的基础研究，但仍然没有食品和药物批准的可卡因药物疗法 使用障碍（CUD）。越来越多的证据表明，先前使用可卡因的历史可能会改变 新 CUD 药物疗法的开发和筛选。我们建议利用翻译效用 临床前药物与非药物选择程序，以确定不同的可卡因自我给药史 影响毒蕈碱乙酰胆碱受体 (mAChR)1 正变构调节剂的有效性 VU0364572 减弱可卡因与食物的选择以及可卡因引起的伏核 (NAc) 增加 使用光纤光度法（即 dLight）释放多巴胺 (DA)。该项目的科学前提是 候选药物可有效减少更广泛实验范围内的药物选择 假设包括可卡因历史在内的条件在临床上更有效。目标1将 确定行为史（即短期与长期可卡因自我给药）对 VU0364572 减弱可卡因与食物选择行为的有效性。在 2 x 4 实验设计中，每个 小组将接受短期获取（ShA）或长期获取（EA）可卡因自我管理条件。 在这两种访问条件下，4种处理（媒介物、0.32、1.0和1.8 mg/kg VU0364572）的效果将 进行评估。目标 2 将确定可卡因历史对 VU0364572 减弱效果的影响 使用 dLight 技术释放可卡因升高的 NAc DA。在 3 x 2 实验设计中，每组将 暴露于三种可卡因获取条件之一（ShA、EA 或未接触过可卡因）且车辆或 VU0364572治疗。使用 dLight 光纤光度测定法，将评估 NAc DA 对可卡因输注的反应。 这些神经化学终点将在各组之间进行比较，并与可卡因对比收集 食物选择数据，允许在受试者内比较神经化学和行为数据。完成 这些研究将测试有关可卡因影响的创新和转化相关假设 mAChR1 PAM 降低可卡因自我给药和可卡因诱导增强功效的历史 中脑边缘 DA 信号传导。