Mechanisms of amphetamine-induced plasticity in adolescents compared to adults

描述(申请人提供)：青春期是人类的一个发育阶段，其特征是个人的生物学和行为发生了巨大的变化。这也是个人可以开始使用精神刺激药物的时期，无论是出于治疗还是娱乐目的。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，这些对认知的不利影响可能会在长期戒毒期间持续存在。因此，了解介导药物诱导的行为变化的神经生物学过程并确定青少年与成年人相比如何特别脆弱是至关重要的。我们在这些研究中的长期目标是了解苯丙胺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。在目标1中，我们将确定mPFC中多巴胺和NMDA受体功能的变化是否与青春期苯丙胺暴露导致的认知行为持久缺陷有关。在目标2中，我们将确定在青少年中观察到的mPFC神经元长期功能变化的基础--与成年接触者相比。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接受测试时，将对药物诱导的认知功能缺陷以及多巴胺和NMDA受体的选择性操作更敏感；2)与成年暴露的个体相比，重复苯丙胺治疗对青春期mPFC神经元的内在放电特性、依赖NMDA的长时程增强以及多巴胺受体介导的反应的影响更大；3)与成年暴露的个体相比，这种暴露对mPFC神经元对苯丙胺和多巴胺或NMDA受体选择性药物的体内反应的影响将更大。这些假说与我们的初步研究一致，该研究表明，青春期暴露于苯丙胺会损害对mPFC敏感的工作记忆任务的行为，并改变体外记录的V层锥体细胞的固有放电特性。通过这项申请中提出的研究，我们试图填补我们知识中的巨大空白，即是什么使青春期的大脑和行为如此独特地不同于成年人，并增加他们对反复接触药物的不良后果的易感性。通过了解青春期大脑的独特可塑性，我们可能会确定预防或治疗策略的目标，旨在改善青春期反复接触苯丙胺的不良后果。此外，我们预计我们的结果将推动该领域更清楚地了解精神刺激剂在这一神经和行为发育的关键时期的独特影响。

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.