Mechanisms of amphetamine-induced plasticity in adolescents compared to adults

描述（由申请人提供）：青春期是人类的一个发展阶段，其特征是个体的生物学和行为发生了巨大变化。这也是一个时期，个人可能开始使用精神兴奋剂药物，无论是为了治疗还是娱乐目的。反复接触这些药物与记忆、决策、冲动控制和奖励处理方面的缺陷有关，这些对认知的不良后果可能会在长期戒断药物后持续存在。因此，了解介导药物引起的行为改变的神经生物学过程，并确定与成年人相比，青少年是如何特别脆弱的，这一点至关重要。我们在这些研究中的长期目标是了解安非他明在青少年大脑皮质边缘区域诱导的神经适应，并确定如何预防或逆转这些变化。在拟议的研究中，我们将在青春期和成年期的动物模型中使用行为、药理学和电生理技术来解决两个目标。在目的1中，我们将确定多巴胺和NMDA受体功能的变化是否与青春期安非他明暴露引起的认知行为持续缺陷有关。在目标2中，我们将确定与成年暴露个体相比，在青少年中观察到的mPFC神经元长期功能变化的基础。我们的工作假设是，1)与成年暴露的大鼠相比，青春期暴露的大鼠在成年后接受测试时，对药物引起的认知功能缺陷和多巴胺和NMDA受体的选择性操作更敏感；2)与成人相比，反复服用安非他明对青少年mPFC神经元的内在放电特性、nmda依赖的长期增强和多巴胺受体介导的反应的影响有所增强；3)这种暴露对mPFC神经元对安非他明和多巴胺或NMDA受体选择性药物的体内反应的影响，在青少年中比在成人中暴露的个体更大。这些假设与我们的初步研究一致，这些研究表明，青春期暴露于安非他命会损害mpfc敏感工作记忆任务的行为，并改变体外记录的V层锥体细胞的内在放电特性。通过本申请中提出的研究，我们试图填补我们知识上的巨大空白，即是什么使青少年的大脑和行为与成年人如此独特地不同，并增加了他们对反复接触药物的不良后果的脆弱性。通过了解青少年大脑的独特可塑性，我们将有可能确定预防或治疗策略的目标，旨在改善青少年时期反复接触安非他明的不良后果。此外，我们预计我们的结果将使该领域更清楚地了解精神兴奋剂在神经和行为发育的关键时期的独特作用。

DESCRIPTION (provided by applicant): Adolescence is a developmental stage in humans that is characterized by dramatic changes in an individual's biology and their behavior. It is also a period during which individuals may begin using psychostimulant drugs, whether for therapeutic or recreational purposes. Repeated exposure to these drugs is associated with deficits in memory, decision making, impulse control, and reward processing, and these adverse consequences on cognition may persist through extended periods of drug abstinence. Thus, it is critically important to understand the neurobiological processes that mediate drug-induced changes in behavior and to determine how adolescents, compared to adults, are particularly vulnerable. Our long-term goal in these studies is to understand the neuroadaptations induced by amphetamine in corticolimbic regions of the adolescent brain and determine how these changes can be prevented or reversed. In the proposed studies, we will use behavioral, pharmacological, and electrophysiological techniques in animal models of adolescence and adulthood to address two aims. In Aim 1, we will determine if changes in dopamine and NMDA receptor function in the mPFC are responsible for the enduring deficits in cognitive behavior induced by amphetamine exposure during adolescence. In Aim 2, we will determine the basis of the long-lasting functional changes in mPFC neurons that are observed in adolescent- compared to adult-exposed individuals. Our working hypotheses are that, 1) adolescent-exposed rats, when tested as adults, will be more sensitive to drug-induced deficits in cognitive function and to selective manipulations of dopamine and NMDA receptors, compared to those exposed as adults; 2) the effects of repeated amphetamine treatment on the intrinsic firing properties, NMDA-dependent long term potentiation, and dopamine receptor-mediated responses of mPFC neurons are enhanced in adolescent- compared to adult-exposed individuals; and 3) the effects of this exposure on the in vivo responses of mPFC neurons to amphetamine and dopamine or NMDA receptor selective drugs will be greater in adolescent- compared to adult-exposed individuals. These hypotheses are consistent with our preliminary studies, which show that that exposure to amphetamine during adolescence impairs behavior on an mPFC-sensitive working memory task and alters the intrinsic firing properties of layer V pyramidal cells recorded in vitro. Through the research proposed in this application, we seek to fill the large gaps in our knowledge about what makes the brain and behavior of adolescence so uniquely different from adults and increases their vulnerability to the adverse consequences of repeated drug exposure. By understanding the unique plasticity of the adolescent brain, we will likely identify targets for preventative or therapeutic strategies aimed at ameliorating the adverse consequences of repeated amphetamine exposure during adolescence. In addition, we anticipate our results will move the field towards a clearer understanding of the unique effects of psychostimulants during this critical period of neural and behavioral development.