Identifying patterns of human polysubstance use to guidedevelopment of rodent models

识别人类多物质使用模式以指导啮齿动物模型的开发

• 批准号: 10224391
• 负责人: Linda B. Cottler
• 金额: $ 51.69万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224391
• 关键词: Abstinence; Acute; Alcohol consumption; Alcohol or Other Drugs use; Alcohols; Animal Model; Area; Attenuated; Back; Behavior; Behavioral Mechanisms; Cannabis; Ceftriaxone; Clinic; Cocaine; Cocaine Dependence; Cocaine Users; Communities; Consumption; Data; Disease; Dopamine; Dopamine Receptor; Epidemiologist; Epidemiology; Extinction (Psychology); FDA approved; Failure; Florida; Glutamates; Goals; High Prevalence; Homeostasis; Human; Infrastructure; Intake; Measures; Mediating; Metabolism; Modeling; Neurobiology; Nucleus Accumbens; Participant; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phased Innovation Awards; Population; Positioning Attribute; Property; Psychometrics; Public Health; Publishing; Rattus; Relapse; Reporting; Rodent Model; Role; Self Administration; Structure; Substance abuse problem; Surveys; Testing; Therapeutic; Time; Translating; Translations; Treatment Efficacy; Typology; University resources; Withdrawal; Work; alcohol availability; alcohol comorbidity; base; clinical efficacy; cocaine relapse; cocaine relapse prevention; cocaine use; cohort; comorbidity; computerized; design; experience; glutamatergic signaling; high risk; human data; human subject; improved; mRNA Expression; marijuana use; neuroadaptation; neurobehavioral; neuromechanism; novel; programs; receptor; receptor expression; recruit; relapse risk; therapeutic target; therapy development; translational pipeline

Project Abstract Cocaine use disorder remains a significant public health problem in the US today, and there is a high risk of relapse even after long periods of abstinence. The current translational pipeline relies on animal models such as the extinction-reinstatement model to screen potential therapies for efficacy at attenuating relapse. While many pharmacological agents successfully reduce cocaine-seeking in this model, these agents show little clinical efficacy, and none have been FDA-approved for cocaine use disorder. One explanation for the failure of these agents to translate to the clinic may lie in the fact that most cocaine users engage in poly-substance use (PSU), while existing animal models of cocaine addiction involve self-administration of cocaine alone. Such PSU likely engages different behavioral and neural mechanisms compared to cocaine alone. Indeed, our preliminary data from a rat model of combined cocaine and alcohol use show that alcohol co-consumption significantly changes the neurobiology supporting cocaine relapse, and renders potential pharmacotherapies ineffective. These data and others highlight the need for a better understanding of PSU. Progress in this area is hampered, however, by a paucity of information regarding how substance (particularly cocaine) users actually engage in PSU. The long- term goal of this project is to determine the unique consequences of PSU on behavior and neurobiology underlying cocaine-seeking. The objectives of the current proposal, which represent the first steps toward our long-term goal, are to 1) develop and validate a survey instrument for evaluating detailed temporal patterns of PSU in cocaine users; 2) determine in a cocaine-using population the most common temporal patterns of alcohol and cannabis use (which are the most frequently used substances in combination with cocaine); 3) back- translate these data to develop rat models of cocaine+alcohol and cocaine+cannabis use; and 4) determine their consequences on neurobiological measures relevant for relapse (glutamate signaling and D2/3 dopamine receptor expression in the nucleus accumbens). Our rationale is that rat models which more closely mimic actual patterns of human substance use should better yield the underlying neuroadaptations present in humans, and should thus serve as better platforms for therapeutic discovery. As such, our central, unified hypothesis is that cocaine users will display high rates of comorbid cocaine+alcohol or cocaine+cannabis use in unique patterns that can be translated into rat models, in which the neurobiology underlying relapse to cocaine-seeking will be altered by such alcohol or cannabis use.

项目摘要 可卡因使用障碍在当今美国仍然是一个重大的公共卫生问题，并且有很高的风险 即使在节制长期后，复发也是如此。当前的翻译管道依赖于动物模型，例如 灭绝的灭绝模型筛选潜在的疗法，以减轻复发的功效。而很多 药理学剂成功地减少了该模型中的可卡因寻求可卡因，这些药物几乎没有临床 功效，没有FDA批准可卡因使用障碍。这些失败的一种解释 转化为诊所的代理商可能在于大多数可卡因使用者从事多种可卡因使用（PSU）， 现有的可卡因成瘾动物模型仅涉及可卡因的自我管理。这样的PSU可能 与仅可卡因相比，与不同的行为和神经机制不同。确实，我们的初步数据 从可卡因和酒精饮酒的大鼠模型中表明，酒精的共同消费会发生显着变化 支持可卡因复发的神经生物学，并使潜在的药物疗法无效。这些数据 其他人则强调需要更好地了解PSU。但是，该领域的进展受到阻碍 关于实质（尤其是可卡因）用户实际参与PSU的信息很少。长期 该项目的术语目标是确定PSU对行为和神经生物学的独特后果 潜在的可卡因寻求。当前提案的目标，代表了迈向我们的第一步 长期目标是1）开发和验证一种调查工具，以评估 可卡因用户的PSU； 2）在使用可卡因人群中确定酒精的最常见时间模式 和大麻的使用（这是最常用的物质与可卡因结合使用）； 3）返回 - 将这些数据转换为开发可卡因+酒精和可卡因+大麻的大鼠模型； 4）确定他们的 与复发相关的神经生物学测量的后果（谷氨酸信号传导和D2/3多巴胺 伏隔核中的受体表达）。我们的理由是，更紧密地模仿实际的大鼠模型 人类物质使用的模式应更好地产生人类中存在的潜在神经照射，并且 因此，应该充当治疗发现的更好平台。因此，我们的中心统一假设是 可卡因用户将显示高可卡因+酒精或可卡因+大麻的速度高 可以将其转化为大鼠模型，其中神经生物学的基本复发将是寻求可卡因的模型 通过这种酒精或大麻的使用改变。