A novel approach for identifying addiction vulnerability in animals.

一种识别动物成瘾脆弱性的新方法。

• 批准号: 9032483
• 负责人: JONATHAN GEWIRTZ
• 金额: $ 16.73万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032483
• 关键词: Accounting; Acute; Affective; Anhedonia; Animal Model; Animals; Anxiety; Behavioral Model; Biological Markers; Chemosensitization; Clinical Research; Comorbidity; Corticosterone; Dependence; Development; Disease; Drug Addiction; Drug Exposure; Drug usage; Elasticity; Extinction (Psychology); Factor Analysis; Freezing; Genetic; Genetic study; Goals; Health; Hormones; Human; Individual; Individual Differences; Injection of therapeutic agent; Investigation; Literature; Measures; Mental Depression; Methodology; Modeling; Molecular Genetics; Morphine; Neurobiology; Opiate Addiction; Opiates; Outcome Measure; Pharmaceutical Preparations; Pre-Clinical Model; Predisposition; Rattus; Reflex action; Research Project Grants; Rodent; Self Administration; Self Stimulation; Severities; Severity of illness; Staging; Strategic Planning; Stress; Structure; Substance Use Disorder; Sum; Testing; Withdrawal; addiction; base; behavior measurement; drug withdrawal; effective therapy; endophenotype; improved; indexing; innovation; negative affect; neuromechanism; novel; novel strategies; pre-clinical; preclinical study; programs; relating to nervous system; response; trait; withdrawal-induced anxiety

 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.

 描述：开发新的物质使用治疗方法取决于理解成瘾易感性和高度合并症（例如焦虑，抑郁症）的个体差异的基础。通过使用验证性因素分析（CFA），这个问题在人类中广泛研究。 CFA识别“潜在”变量（未直接测量的变量）反映了大量相关措施之间的共同方差。这些潜在变量比单个测量值具有更大的统计可靠性，并充当神经生物学和遗传研究的靶标，以开发生物标志物并改善治疗方法。尽管CFA在临床前研究中几乎没有使用，但它在临床研究中的广泛应用，但从未应用于成瘾和合并症的动物模型。该建议将使用CFA来识别潜在变量的基础变量 在大鼠中，在验证自我给药（SA）的可靠性方面的个体差异，并确定哪些因素与对Anhedonia的易感性最紧密相关或在戒断过程中引起了焦虑。 Opite SA的承诺将通过多种SA（包括获取，需求和恢复）的多种测量来评估。在药物SA测试之前和完成时，将测量从急性吗啡注射中提取。 Anhedonia将被衡量为颅内自刺激阈值的高程，而动画则是惊吓反射和冻结的潜力。假设：1）优化SA的不同度量之间的可变性最好由一个或多个优化SA的潜在变量来解释； 2）提款引起的抗消毒和动画将与更优化的SA承诺相关联。即使在药物暴露有限之后，这种关联也将是证据，这表明初始药物使用期间的负面反应反映了成瘾责任的潜在特征。 3）Anhedonia的严重程度和在药物戒断过程中的焦虑症也将与单独的药物SA（例如，需求的弹性与应力诱导的恢复原状的弹性）最密切相关。该提议完全是创新的，试图表征疾病严重程度的潜在结构及其关系，这些结构来自毒品SA和戒断的多个临床前指标。识别这种结构将为旨在开发更有效治疗的遗传，分子和药物研究提供关键的靶标。该提议在表征焦虑和抗药对药物SA的个体差异的不同贡献以及测试戒断引起的负面影响的有效性作为成瘾的早期标志的有效性方面也具有创新性。通过提高毒品SA承诺的测量的可靠性，并利用人类文献中已经确定的方法，该提议有望提供临床前成瘾模型，并具有更大的预测性和构造有效性。总而言之，在调整CFA的强大方法以确定与啮齿动物中强迫性吸毒和戒毒相关的最关键变量时，我们的建议非常适合CEBRA计划的主要目标。

项目成果

Higher anhedonia during withdrawal from initial opioid exposure is protective against subsequent opioid self-administration in rats.

在大鼠中，从最初的阿片类药物暴露戒断期间较高的快感缺乏可以防止随后的阿片类药物自我给药。

• DOI: 10.1007/s00213-020-05532-w
• 发表时间: 2020
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: Swain,Yayi;Muelken,Peter;Skansberg,Annika;Lanzdorf,Danielle;Haave,Zachary;LeSage,MarkG;Gewirtz,JonathanC;Harris,AndrewC
• 通讯作者: Harris,AndrewC

Locomotor activity does not predict individual differences in morphine self-administration in rats.

运动活动并不能预测大鼠吗啡自我给药的个体差异。

• DOI: 10.1016/j.pbb.2018.01.008
• 发表时间: 2018
• 期刊: Pharmacology, biochemistry, and behavior
• 作者: Swain,Yayi;Muelken,Peter;LeSage,MarkG;Gewirtz,JonathanC;Harris,AndrewC
• 通讯作者: Harris,AndrewC