PRECLINICAL STUDIES:ANIMAL MODELS OF IMPULSIVITY AND ADDICTION

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 冲动行为滥用药物实验将产生可直接翻译给人类的信息 药物滥用预防和治疗。大脑成像研究将使我们能够检查潜在的 神经生物学机制，并将结果与人脑成像结果进行比较。主要问题是 讨论的是冲动是否与过度的药物，食物和其他物质的使用有关， 磁共振成像（MRI）揭示神经生物学与冲动和成瘾的相关性？组 的大鼠将包括那些选择了高（H）或低（L）冲动的延迟折扣（DD）任务的大鼠， 可卡因（HiC，LoC）或食物（Mil，Lol）和其他将被选择性地培育用于高和低摄入糖精 解决方案（HiS，LoS）。这些组将进行比较：1）基于可卡因或食物的认知冲动 在DD任务中，提供较大的延迟与较小的即时奖励或运动冲动之间的选择- 抑制对可卡因或食物奖励的运动行为的能力受损（Go/No-go），2）可卡因的增加 自我给药，3）可卡因寻求行为的恢复（复发），4）GABA相关药物的有效性 治疗药物，和5）对甜液体的偏好，药物滥用的预测因素。具体 目的是：1）研究延迟折扣，作为一个因素，促进药物滥用的雄性和雌性大鼠 和成瘾倾向（与抗性）表型（HiC，LoC; Hil，Lol; HiS，LoS）。神经影像学研究将 在暴露于可卡因之前对各组进行研究，以确定 与行为结果相关，以及人类研究的结果（项目2和3），2）研究运动 （反应抑制）方面的冲动行为在成瘾倾向和。 Go/No-go任务，涉及信号Go（奖励）和No-go（未奖励）组件。响应 在No-go组件期间表示抑制控制失败。这些发现将与 成像结果和人类研究（项目2和3），3）为了研究冲动相关的差异， 可卡因摄入量增加中的成瘾倾向表型，4）模拟药物寻求的恢复， 确定冲动相关的差异，成瘾倾向表型是如何转化为最 药物滥用的挑战性方面，复发。5)为了检查与GABA相关的托吡酯治疗的效果， 药物，可卡因自我管理的冲动相关，成瘾倾向，耐药表型 (e.g.,女性，男性; HiC，LoC; Hil，Lol;和HiS，LoS），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，这是很难在人类中研究，并测试针对GABA系统的治疗。

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.