A novel approach for identifying addiction vulnerability in animals.

 产品说明：开发物质使用障碍的新治疗方法取决于对成瘾和高度共病障碍（例如，焦虑、抑郁）。这个问题已经通过使用验证性因素分析（CFA）在人类中进行了广泛的研究。验证性因素分析确定了“潜在”变量（未直接测量的变量），反映了大量相关测量中的共同方差。这些潜在变量具有比单独测量更大的统计可靠性，并作为神经生物学和遗传学研究的目标，以开发生物标志物并改善治疗。尽管CFA在临床研究中得到了广泛应用，但它几乎没有被用于临床前研究，也从未被应用于成瘾和合并症的动物模型中。本提案将使用验证性因素分析来确定潜在变量， 个体差异的倾向阿片自我管理（SA）在大鼠中，并确定哪些因素是最密切相关的易感性快感缺失或焦虑引起的阿片戒断。阿片类药物SA倾向将通过吗啡SA的多项指标进行评估，包括获得、需求和恢复。将在药物SA测试之前和完成时测量急性吗啡注射的戒断。快感缺失将被测量为颅内自我刺激阈值的升高，焦虑将被测量为惊吓反射和冻结的增强。假设：1）阿片类物质SA的不同测量之间的变异性将最好地由阿片类物质SA倾向的一个或多个潜在变量来解释; 2）戒断诱导的快感缺失和焦虑将与更大的阿片类物质SA倾向相关。即使在有限的药物暴露后，这种关联也将是明显的，这表明初始药物使用期间的负面情感反应反映了预测成瘾倾向的潜在特征; 3）戒断期间快感缺失和焦虑的严重程度也将与药物SA的单独测量最强烈地相关（例如，需求弹性与压力引起的恢复）。该提案在寻求从药物SA和戒断的多个临床前指标表征疾病严重程度的基本结构及其关系方面是完全创新的。这些构建体的鉴定将为旨在开发更有效的治疗方法的遗传、分子和药理学研究提供关键的靶点改进。这一建议也是创新的特征的焦虑和快感缺乏的个体差异，在药物SA的独特贡献，并在测试的有效性，撤药引起的负面影响作为成瘾的早期标志。通过增加药物SA倾向的测量的可靠性，并通过利用在人类文献中已经很好地建立的方法，预计该提议将提供具有更大预测性和结构有效性的成瘾临床前模型。总之，在适应CFA的强大的方法，以确定最关键的变量与啮齿动物的强迫性药物使用和药物戒断，我们的建议是非常合适的CEBRA计划的主要目标。

 DESCRIPTION: Developing new treatments for substance use disorders depends on understanding the basis of individual differences in susceptibility to addiction and highly comorbid disorders (e.g., anxiety, depression). This issue has been widely studied in humans through the use of Confirmatory Factor Analysis (CFA). CFA identifies "latent" variables (variables that are not measured directly) reflecting the common variance among a larger number of related measures. These latent variables have greater statistical reliability than individual measures and serve as targets of neurobiological and genetic studies to develop biomarkers and improve treatments. Despite its widespread application in clinical research, CFA has been virtually unused in preclinical studies and has never been applied in animal models of addiction and comorbidity. This proposal will use CFA to identify the latent variable(s) underlying individual differences in propensity for opiate self-administration (SA) in rats, and determine which factors are most closely associated with susceptibility to anhedonia or anxiety elicited during opiate withdrawal. Opiate SA propensity will be assessed through a number of measures of morphine SA including acquisition, demand, and reinstatement. Withdrawal from acute morphine injections will be measured both prior to and at the completion of drug SA testing. Anhedonia will be measured as elevations in intracranial self-stimulation thresholds, and anxiety as potentiation of the startle reflex and freezing. Hypotheses: 1) Variability among different measures of opiate SA will be best accounted for by one or more latent variables of opiate SA propensity; 2) Withdrawal-induced anhedonia and anxiety will be associated with greater opiate SA propensity. This association will be evident even after limited drug exposure, suggesting that negative affective responses during initial drug use reflect an underlying trait predictive of addiction liability; 3) Severity of anhedonia and anxiety during drug withdrawal will also be associated most strongly with separate measures of drug SA (e.g., elasticity of demand versus stress-induced reinstatement). This proposal is entirely innovative in seeking to characterize underlying constructs of disease severity, and their relationships, from multiple preclinical indices of drug SA and withdrawal. Identification of such constructs will provide critical refinements of targets for genetic, molecular, and pharmacological investigations aimed at developing more effective treatments. This proposal is also innovative in characterizing the distinct contributions of anxiety and anhedonia to individual differences in drug SA, and in testing the validity of withdrawal-induced negative affect as an early marker for addiction. By increasing the reliability of measures of drug SA propensity, and by utilizing an approach that is already well established in the human literature, this proposal is expected to provide preclinical models of addiction with greater predictive and construct validity. In sum, in adapting the powerful approach of CFA to identify the most critical variables associated with compulsive drug use and drug withdrawal in rodents, our proposal is highly appropriate to the primary goals of the CEBRA program.