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

基本信息

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
项目类别：
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

项目摘要

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）：青春期是人类的发展阶段，其特征是个人的生物学及其行为发生了巨大变化。这也是个人可以开始使用心理刺激药物的时期，无论是出于治疗或娱乐目的。反复接触这些药物与记忆，决策，冲动控制和奖励处理中的缺陷有关，而这些对认知的不利后果可能会通过延长的药物戒酒时期持续存在。因此，了解介导药物引起的行为变化并确定青少年与成年人相比特别脆弱的神经生物学过程至关重要。在这些研究中，我们的长期目标是了解青少年大脑的皮质降环苯丙胺引起的神经适应性，并确定如何预防或反转这些变化。在拟议的研究中，我们将在青春期和成年的动物模型中使用行为，药理和电生理技术来解决两个目标。在AIM 1中，我们将确定MPFC中多巴胺和NMDA受体功能的变化是否负责青春期苯丙胺暴露引起的认知行为的持久缺陷。在AIM 2中，我们将确定与成人暴露的个体相比，在青少年中观察到的MPFC神经元的持久功能变化的基础。我们的工作假设是，1）与成年人相比，与暴露于成年人相比，在成年人中进行测试时，将对药物诱导的缺陷以及多巴胺和NMDA受体的选择性操纵更为敏感。 2）与成人暴露的个体相比，青少年的重复苯丙胺治疗对MPFC神经元的内在点火特性，NMDA依赖性长期增强和多巴胺受体介导的反应的影响增强了； 3）与成人暴露的个体相比，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更大。这些假设与我们的初步研究一致，这些假设表明，在青春期中暴露于苯丙胺会损害MPFC敏感的工作记忆任务上的行为，并改变了体外记录的V层V锥体细胞的固有激发特性。通过本申请中提出的研究，我们试图填补有关使青春期大脑和行为与成年人如此独特的知识的巨大差距，并增加了他们对重复药物暴露的不利后果的脆弱性。通过了解青春期大脑的独特可塑性，我们可能会确定旨在改善青春期反复苯丙胺暴露的不利后果的预防或治疗策略的靶标。此外，我们预计我们的结果将使该领域更清楚地了解心理刺激物在神经和行为发展的关键时期。