Mechanisms of amphetamine-induced plasticity in adolescents compared to adults

与成人相比，安非他明诱导青少年可塑性的机制

• 批准号: 8603853
• 负责人: Joshua M Gulley
• 金额: $ 30.5万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8603853
• 关键词: Address; Adolescence; Adolescent; Adolescent Development; Adult; Adverse effects; Age; Amphetamines; Animal Model; Animals; Behavior; Behavioral; Biology; Brain; Brain region; Cognition; Cognitive; Cognitive deficits; Data; Decision Making; Development; Dopamine Receptor; Drug Exposure; Exposure to; Goals; Human; In Vitro; Individual; Knowledge; Left; Life; Literature; Long-Term Potentiation; Medial; Mediating; Memory; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurobiology; Neurons; Neurosciences; Outcome; Performance; Pharmaceutical Preparations; Prefrontal Cortex; Prevention strategy; Process; Property; Pyramidal Cells; Rattus; Research; Role; Saline; Short-Term Memory; Slice; Staging; Structure; Techniques; Testing; Therapeutic; Work; adverse outcome; base; behavioral impairment; brain behavior; cognitive function; critical period; drug abstinence; in vivo; neuroadaptation; preclinical study; prevent; psychostimulant; public health relevance; receptor; receptor function; relating to nervous system; research study; response; reward processing

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.

描述（由申请人提供）：青春期是人类的一个发育阶段，其特征是个体的生物学和行为发生巨大变化。这也是个人可能开始使用精神兴奋剂药物的时期，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的缺陷有关，这些对认知的不良后果可能会持续到药物戒断的延长期。因此，至关重要的是要了解介导药物引起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。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引起的神经适应，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，药理学和电生理学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是青春期安非他明暴露引起的认知行为持久缺陷的原因。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-与成人暴露个体相比。我们的工作假设是：1）与成年暴露的大鼠相比，成年暴露的大鼠对药物诱导的认知功能缺陷和对多巴胺和NMDA受体的选择性操纵更敏感; 2）重复安非他明处理对固有放电特性、NMDA依赖的长时程增强、与成年暴露个体相比，青少年mPFC神经元的多巴胺受体介导的反应增强;和3）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在青少年中更大-与成年人相比。这些假设与我们的初步研究是一致的，这些研究表明，在青春期暴露于安非他明损害行为的mPFC敏感的工作记忆任务，并改变了内在的放电特性的第五层锥体细胞记录在体外。通过本申请中提出的研究，我们试图填补我们知识中的巨大空白，了解是什么使青少年的大脑和行为与成年人如此独特，并增加了他们对重复药物暴露不良后果的脆弱性。通过了解青少年大脑独特的可塑性，我们将有可能确定预防或治疗策略的目标，旨在改善青春期反复接触安非他明的不良后果。此外，我们预计我们的研究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。