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.

项目摘要 每年与可卡因相关的过量死亡人数增加，可卡因滥用是一个严重的公共健康问题。 尽管进行了数十年的基础研究，但仍然没有可卡因的食品和药物批准的药物治疗 使用障碍（CUD）。越来越多的证据表明，先前的可卡因使用历史可能会改变 开发和筛查新的CUD药物治疗。我们建议利用 临床前药物vs-nondrug选择程序，以确定不同可卡因自我管理历史如何 影响毒蕈碱乙酰胆碱受体（MACHR）1阳性变构调节剂的有效性 VU0364572减轻可卡因VS食品的选择和可卡因诱导的伏隔核的增加（NAC） 多巴胺（DA）使用纤维光度法（即Dlight）释放。该项目的科学前提是 在更广泛的实验范围内有效减少药物选择有效的候选药物 包括可卡因历史在内的条件将在临床上更有效。目标1意志 确定行为史（即短与访问可卡因自我管理）的影响 VU0364572减弱可卡因VS食品选择行为的有效性。在2 x 4的实验设计中，每个设计 小组将经历短期访问（SHA）或扩展访问（EA）可卡因自我管理条件。 在这两个访问条件下，4种治疗的影响（车辆，0.32、1.0和1.8 mg/kg VU0364572）将 被评估。 AIM 2将确定可卡因历史对VU0364572的有效性的影响 使用Dlight技术释放可卡因的NAC DA。在3 x 2实验设计中，每组将是 暴露于三种可卡因通道条件之一（SHA，EA或可卡因幼稚）和车辆或车辆或 VU0364572处理。使用Dlight纤维光度法，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VS-一起收集 食物选择数据，允许对神经化学和行为数据的受试者内部比较。完成 这些研究将检验有关可卡因影响的创新和翻译相关的假设 MACHR1 PAM效率的历史记录以降低可卡因自我给药和可卡因诱导的增强 中唇型DA信号传导。