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：开发药物滥用障碍的新疗法取决于了解成瘾和高度共存疾病（例如焦虑、抑郁）的个体差异的基础，这一问题已通过使用验证性因素分析（CFA）在人类中进行了广泛研究。 CFA 识别出“潜在”变量（不直接测量的变量），这些变量反映了大量相关测量之间的共同方差，这些潜在变量比单独的测量具有更高的统计可靠性，并可作为测量的目标。尽管 CFA 在临床研究中得到了广泛应用，但它尚未用于成瘾和合并症的动物模型，该提案实际上将使用 CFA 来识别潜在变量。 (s) 底层 大鼠阿片类药物自我给药（SA）倾向的个体差异，并确定哪些因素与阿片类药物戒断期间引起的快感缺乏或焦虑最密切相关。阿片类药物 SA 倾向将通过吗啡 SA 的多种测量（包括获取）进行评估。 、需求和恢复情况将在药物 SA 测试之前和完成时测量。自我刺激阈值以及焦虑作为惊吓反射和冻结的增强 假设：1）阿片类镇静剂不同测量值之间的差异最好由阿片类镇静剂倾向的一个或多个潜在变量来解释；2）戒断引起的快感缺乏和即使在有限的药物暴露后，焦虑也会与更大的阿片类药物倾向相关，这表明最初使用药物期间的负面情感反应反映了成瘾倾向的潜在特征3）；药物戒断期间快感缺乏和焦虑的严重程度也与药物 SA 的单独测量密切相关（例如，需求弹性与压力诱导的恢复）。该提案在寻求描述疾病严重程度的基本结构及其特征方面是完全创新的。从药物 SA 和戒断的多个临床前指标中确定这些结构的关系将为遗传、分子和药理学研究提供关键的靶点，旨在开发更有效的治疗方法。通过提高药物 SA 倾向测量的可靠性，并利用已经建立的方法，研究焦虑和快感缺乏对药物 SA 个体差异的影响，并测试戒断引起的负面影响作为成瘾早期标志的功效。在人类文献中，该提议有望提供具有更大预测和构建有效性的成瘾临床前模型。总之，在采用 CFA 的强大方法来识别与啮齿类动物强迫性药物使用和药物戒断相关的最关键变量时，我们的研究。提案非常适合CEBRA 计划的主要目标。

项目成果

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。

• 发表时间: 2018-03
• 作者: Swain, Yayi;Muelken, Peter;LeSage, Mark G;Gewirtz, Jonathan C;Harris, Andrew C
• 通讯作者: Harris, Andrew C

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。

• 发表时间: 2020-08
• 影响因子: 3.4
• 作者: Swain, Yayi;Muelken, Peter;Skansberg, Annika;Lanzdorf, Danielle;Haave, Zachary;LeSage, Mark G;Gewirtz, Jonathan C;Harris, Andrew C
• 通讯作者: Harris, Andrew C