Identifying patterns of human polysubstance use to guidedevelopment of rodent models

项目摘要 可卡因使用障碍在今天的美国仍然是一个严重的公共卫生问题，而且有很高的风险 即使在长期禁欲之后也会复发。目前的翻译管道依赖于动物模型，如 消退-恢复模型，以筛选减少复发的潜在治疗方法。虽然很多人 在这个模型中，药理药物成功地减少了可卡因的寻求，这些药物几乎没有临床表现。 疗效，没有一种是FDA批准的可卡因使用障碍。对这些失败的一种解释 转化到临床的药物可能在于大多数可卡因使用者从事多物质使用(PSU)的事实， 而现有的可卡因成瘾动物模型只涉及自身给药。这样PSU可能 与单独使用可卡因相比，它具有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，酒精的共同消费显著改变 神经生物学支持可卡因复发，并使潜在的药物治疗无效。这些数据 其他人则强调了更好地理解PSU的必要性。然而，这一领域的进展受到以下因素的阻碍 缺乏关于物质(特别是可卡因)使用者实际如何参与PSU的信息。长的- 本项目的学期目标是确定PSU对行为和神经生物学的独特影响。 潜在的可卡因寻觅。当前提案的目标，代表着迈向我们 长期目标是1)开发和验证用于评估详细的时间模式的调查工具 可卡因使用者的PSU；2)在可卡因使用人群中确定最常见的酒精时间模式 和大麻的使用(这是与可卡因结合在一起最常用的物质)；3)返回- 将这些数据转化为发展可卡因+酒精和可卡因+大麻使用的大鼠模型；以及4)确定它们的 与复发相关的神经生物学措施的后果(谷氨酸信号和D2/3多巴胺 伏隔核内受体的表达)。我们的理论基础是大鼠模型更接近于实际情况 人类物质的使用模式应该更好地产生人类存在的潜在神经适应，以及 因此，应该成为治疗发现的更好平台。因此，我们的中心统一假设是 可卡因吸毒者将以独特的模式显示出高比例的可卡因+酒精或可卡因+大麻的使用 这可以转化为大鼠模型，在模型中，复发到寻求可卡因的神经生物学基础将是 因使用酒精或大麻而改变的。

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.