Behavior Consequences of Amphetamine Dependence in Mice

描述（由申请人提供）：药物滥用和依赖仍然是美国的一个主要健康和社会问题。早期关于药物滥用的实验室研究集中在滥用药物的直接回报（欣快感）或厌恶（戒断症状）后果上，以解释持续的非法药物使用。作为对“药物渴求”的一致临床报告的回应，实验室研究人员也研究了滥用药物对大脑基本奖励和联想系统的直接影响。然而，对欣快感、戒断症状或渴望的耐受性不是精神病学对药物滥用或依赖定义的必要或充分条件。对《精神障碍诊断和统计手册》的审查表明，这些综合征的一个突出特征是扰乱学校、工作和/或社会（个人和/或法律）行为。这种替代行为的中断被认为是对更有回报和强迫诱导的药物的反应而发生的优先级重组。行为致敏研究表明，成瘾药物可以改变多巴胺（DA）和其他神经递质系统。其他研究表明，其中一些DA系统不仅调节药物奖励，还调节其他自然奖励（食物、性和避免伤害）的预期和条件行为。本研究的目的是建立一种小鼠行为模型，研究慢性间歇性药物暴露对工作奖励的影响。目的1将确定C57BL/6J小鼠在非药物环境中为奖励工作是否会被单独的不同环境中的间歇性重复安非他明（AMPH）改变。目标2将确定这些间接影响是否在AMPH停止后持续存在。在药物相关环境中AMPH致敏和停药后，Aim 3将确定在先前的工作环境中低剂量的AMPH是否会对致敏和未致敏的C57BL/6J小鼠产生不同的增强反应。这些实验的最终目标是在一个物种中产生从物质暴露到物质依赖过渡的动物模型，这将允许多层次的方法（行为，药理学和遗传学）来发现导致药物依赖发展的机制。

DESCRIPTION (provided by applicant): Drug abuse and dependence continue to be a major health and social problem in the United States. Early laboratory research on drug abuse has focused on the directly rewarding (euphoria) or aversive (withdrawal symptoms) consequences of abused drugs to explain persistent illegal drug use. In response to consistent clinical reports of "drug craving", laboratory researchers have also examined the direct effects that abused drugs have on basic reward and associative systems of the brain. However, tolerance to euphoria, withdrawal symptoms, or craving is not necessary or sufficient to the psychiatric definition of Substance Abuse or Dependence. Review of the "Diagnostic and Statistical Manual of Mental Disorders" shows that a prominent feature of these syndromes is the disruption of school, work, and/or social (personal and/or legal) behaviors. This disruption of alternative behaviors is thought to occur as a reorganization of priorities in response to a more rewarding and compulsion-inducing drug. Behavioral sensitization research has shown that addictive drugs can change dopamine (DA) and other neurotransmitter systems. Other research has shown that some of these same DA systems mediate not only drug reward, but also anticipatory and conditioned behavior for other natural rewards (food, sex, and avoidance of harm). The purpose of this proposal is to develop a mouse behavioral model of the effects of chronic intermittent drug exposure on working for rewards. Aim 1 will determine if working for a reward in a non-drug environment will be changed by intermittent repeated amphetamine (AMPH) in a separate distinct environment in C57BL/6J mice. Aim 2 will determine if these indirect effects persist after AMPH ceases. After AMPH sensitization and withdrawal in the drug-related environment, Aim 3 will determine if low doses of AMPH in the previous work environment will augment responding differently for sensitized versus unsensitized C57BL/6J mice. The ultimate goal of these experiments is to generate an animal model of the transition from substance exposure to Substance Dependence in a species that will allow for multi-level approaches (behavioral, pharmacological and genetic) to the discovery of mechanisms that contribute to the development of drug dependence.