Identifying patterns of human polysubstance use to guidedevelopment of rodent models

项目摘要 可卡因使用障碍仍然是当今美国的一个重大公共卫生问题，并且存在高风险。 即使在长时间禁欲后也会复发。目前的翻译管道依赖于动物模型，如 预防-恢复模型，以筛选潜在的治疗方法在减轻复发方面的疗效。虽然许多 药理学试剂成功地减少了可卡因寻求在这个模型中，这些试剂显示很少的临床 疗效，没有一个被FDA批准用于可卡因使用障碍。这些失败的一个解释是， 代理翻译到诊所可能在于大多数可卡因使用者从事多种物质使用（PSU）的事实， 而现有的可卡因成瘾的动物模型涉及单独的可卡因自我给药。这样的PSU可能 与单独使用可卡因相比，使用了不同的行为和神经机制。事实上，我们的初步数据 从可卡因和酒精联合使用的大鼠模型显示， 神经生物学支持可卡因复吸，并使潜在的药物治疗无效。这些数据 和其他人强调需要更好地了解PSU。然而，这一领域的进展受到下列因素的阻碍： 缺乏关于物质（特别是可卡因）使用者实际上如何参与PSU的信息。很长的- 本项目的长期目标是确定PSU对行为和神经生物学的独特影响 潜在的可卡因寻求者目前提案的目标是， 长期目标是：1）开发和验证一种调查工具，用于评估 可卡因使用者的PSU; 2）确定可卡因使用人群中最常见的酒精时间模式 和大麻的使用（这是与可卡因结合使用最频繁的物质）; 3）回来- 将这些数据转化为可卡因+酒精和可卡因+大麻使用的大鼠模型;以及4）确定它们的 对与复发相关的神经生物学指标（谷氨酸信号传导和D2/3多巴胺）的影响 受体在丘脑核中的表达）。我们的理论是，更接近模拟实际情况的大鼠模型 人类物质使用的模式应该更好地产生人类存在的潜在神经适应， 因此应该成为发现治疗方法的更好平台。因此，我们的核心统一假设是， 可卡因使用者将以独特的模式显示出高比例的可卡因+酒精或可卡因+大麻使用共病 这可以转化为大鼠模型，其中可卡因寻求复发的神经生物学基础将是 通过使用酒精或大麻来改变。

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.