PRECLINICAL STUDIES:ANIMAL MODELS OF IMPULSIVITY AND ADDICTION

临床前研究：冲动和成瘾的动物模型

• 批准号: 7647108
• 负责人: Marilyn E. Carroll
• 金额: $ 26.08万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7647108
• 关键词: Address; Alcohol or Other Drugs use; Animal Model; Animals; Behavior; Behavior Therapy; Behavioral; Behavioral Model; Brain imaging; Breeding; Cocaine; Cognitive; Dose; Drug abuse; Effectiveness; Exposure to; Extinction (Psychology); Failure; Female; Food; GABA Agonists; Human; Image; Imaging Techniques; Impulsive Behavior; Impulsivity; Individual Differences; Intake; Learning; Liquid substance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Modeling; Motor; Neurobiology; Pharmaceutical Preparations; Phenotype; Procedures; Rattus; Relapse; Resistance; Rewards; Saccharin; Saline; Screening procedure; Self Administration; Signal Transduction; Simulate; Solutions; System; Testing; Time; Training; Translating; Treatment outcome; addiction; base; behavior measurement; day; design; discount; discounting; drug abuse prevention; drug seeking behavior; gamma-Aminobutyric Acid; human prostaglandin D2 receptor; human study; innovation; male; men' s group; neurobiological mechanism; neuroimaging; pre-clinical; preclinical study; preference; research study; response; success; topiramate; treatment effect

The overall objective of this project is to use innovative animal models and imaging techniques to study impulsive behavior drug abuse. Experiments will yield information that will be directly translatable to human drug abuse prevention and treatment. Brain imaging studies will allow us to examine underlying neurobiological mechanisms and compare results to human brain imaging results. The main questions to be addressed are whether impulsivity is related to excessive drug, food, and other substance use, and does magnetic resonance imaging (MRI) reveal neurobiological correlates with impulsivity and addiction? Groups of rats will consist of those selected with a delay-discounting (DD) task for high (H) or low (L) impulsivity for cocaine (HiC, LoC) or food (Mil, Lol) and others will be selectively bred for high and low intake of a saccharin solution (HiS, LoS). These groups will be compared on: 1) Cognitive impulsivity for cocaine or food based on a DD task offering a choice between a larger delayed vs. smaller immediate reward, or motor impulsivity - impaired ability to inhibit motor action toward a cocaine or food reward (Go/No-go), 2) Escalation of cocaine self-administration, 3) Reinstatement of cocaine-seeking behavior (relapse), 4) Effectiveness of a GABArelated treatment drug, and 5) Preference for a sweetened liquid, a predictor of drug abuse. The Specific Aims are: 1) To examine delay-discounting, as a factor contributing to drug abuse in male and female rats and the addiction-prone (vs. resistant) phenotypes (HiC, LoC; Hil, Lol; HiS, LoS). Neuroimaging studies will be conducted on the groups before exposure to cocaine to identify neurobiological mechanisms that are associated with behavioral results, and results from the human studies (Projects 2 and 3), 2) To study motor (response inhibition) aspects of impulsive behavior in the addiction-prone and .Airesistant groups using the Go/No-go task that involves signaled Go (rewarded) and No-go (unrewarded) components. Responding during the No-go components represents failure of inhibitory control. These findings will be related to the imaging results and human studies (Projects 2 and 3), 3) To investigate differences in impulsivity-related, addiction-prone phenotypes in the escalation of cocaine intake, 4) To model reinstatement of drug-seeking to determine how differences in impulsivity-related, addiction-prone phenotypes are translated to the most challenging aspect of drug abuse, relapse. 5) To examine the effects of treatment with topiramate, a GABArelated drug, on cocaine self-administration in the impulsivity-related, addiction-prone, -resistant phenotypes (e.g., female, male; HiC, LoC; Hil, Lol; and HiS, LoS, respectively), and treatment success will be related to the imaging results. These studies will allow us to relate impulsive behavior to several different aspects of drug abuse that are difficult to study in humans and to test treatments targeted at the GABA system.

该项目的总体目标是使用创新的动物模型和成像技术来研究 冲动行为吸毒。实验将产生可直接翻译给人类的信息 预防和治疗药物滥用。脑成像研究将使我们能够检查潜在的 并将结果与人脑成像结果进行比较。要解决的主要问题是 关于冲动是否与过度使用药物、食物和其他物质有关，以及是否 核磁共振成像(MRI)揭示了神经生物学与冲动和成瘾的相关性？群组 将包括那些被选为高(H)或低(L)冲动的延迟折扣(DD)任务的大鼠 将有选择地培育可卡因(HIC，LoC)或食物(Mil，Lol)等，以适应糖精的高和低摄入量 解决方案(他的，洛杉矶)。这些组将在以下方面进行比较：1)对可卡因或基于食物的认知冲动 在一个DD任务上，提供了一个选择，要么是更大的延迟奖励，要么是更小的即时奖励，或者是运动冲动-- 抑制对可卡因或食物奖励的运动动作的能力受损(去/不去)，2)可卡因的升级 自我管理，3)恢复寻求可卡因的行为(复发)，4)与GABA相关的有效性 治疗药物，以及对甜味液体的偏爱，这是药物滥用的预测因素。具体的 目的是：1)检查延迟折扣作为导致雄性和雌性大鼠滥用药物的一个因素 以及易成瘾(与抵抗)表型(Hic，LoC；Hil，Lol；His，Los)。神经成像研究将 在接触可卡因之前对这些组进行检查，以确定神经生物学机制 与行为结果和人体研究(项目2和3)的结果有关，2)研究运动 (反应抑制)易上瘾和抗上瘾人群中冲动行为的方面 进行/不进行任务，包括发信号的进行(奖励)和不进行(不奖励)组件。正在响应 在不去的时候，成分代表抑制控制的失败。这些发现将与 成像结果和人体研究(项目2和3)，3)调查与冲动相关的差异， 可卡因摄入量增加中易上瘾的表型，4)恢复寻求药物的模型 确定冲动相关、容易上瘾的表型的差异是如何转化为最大的 毒品滥用的挑战性方面，复发。5)检查与GABA相关的托吡酯的治疗效果 药物、可卡因自我给药在冲动相关、易成瘾、耐药表型中的作用 (例如，分别为女性、男性；HIC、LOC；HIL、LOL；以及HIS、LOS)，并且治疗成功将与 成像结果。这些研究将使我们能够将冲动行为与以下几个不同方面联系起来 药物滥用很难在人体上进行研究，也很难测试针对GABA系统的治疗方法。