Methamphetamine effects on cognition and 5-HT receptors in orbitofrontal cortex

描述(申请人提供)：青春期是儿童和成人之间的过渡期，在此期间大多数药物使用开始。在青春期开始使用药物，女性与男性相比，与较差的长期结果有关，如认知缺陷增加和转变为依赖的可能性。为了解决我们对可能导致青少年和女性成瘾易感性增加的机制的认识差距，重要的是了解弱势群体(例如青少年和女性)典型的寻求药物的模式，以及药物诱导的长期神经适应和执行功能的变化。这里提出的研究的长期目标是确定行为和神经生物学机制，这些机制可能是青少年和女性甲基苯丙胺(甲基苯丙胺)使用者对药物依赖的易感性增加的基础。这些实验将在大鼠模型中使用行为、药理学和免疫组织化学技术来评估两个特定的目标。目的1将通过检查静脉注射冰毒自我给药的各个方面，如当冰毒不可用时的反应，获得冰毒的动机，消退反应，以及5-HT2CR操作对线索恢复的调节，来描述不适应药物寻求的年龄和性别特征，并通过检查静脉注射冰毒自我给药的各个方面来研究复发增加的机制。目标2将确定冰毒自我管理对认知灵活性的影响，并评估一种机制--眼眶额叶皮质中改变的5-HT2CRs--通过该机制，观察到的缺陷可能会显现出来。培训目标的实现包括获得基础神经生物学技术方面的各种技能和成瘾神经科学领域的专业发展，将通过课程作业和阅读资料、向具有拟议技术专长的个人进行实践培训、参加讲习班、研讨会和国家会议以及每月与培训小组举行会议来实现这些目标。拟议的研究结果将推动该领域更清楚地了解毒品使用的前因和后果，这些因素会增加高危人群的成瘾脆弱性。建议的实验结果可以用来促进为女性和青少年使用者制定个性化的预防和治疗策略，因为他们向依赖过渡的风险更高。

DESCRIPTION (provided by applicant): Adolescence is a transitional period between childhood and adulthood, during which most drug use begins. Drug use initiated during adolescence, and in females compared to males, is associated with poorer long-term outcomes, such as increased cognitive deficits and likelihood to transition to dependence. To address our gap in knowledge of the mechanisms that may confer enhanced addiction vulnerability in adolescents and females, it is important to understand the patterns of drug seeking typical of vulnerable populations (e.g. adolescents and females) and the long-lasting drug-induced neuroadaptations and changes in executive functioning. The long-term goal of the studies proposed here is to identify behavioral and neurobiological mechanisms that may underlie heightened vulnerability to drug dependence in adolescent-onset and female methamphetamine (METH) users. The experiments will employ behavioral, pharmacological, and immunohistochemical techniques in a rat model to assess two specific aims. Aim 1 will characterize age- and sex-specific patterns of maladaptive drug seeking and investigate a mechanism of heightened relapse by examining aspects of intravenous METH self-administration, such as responding when METH is unavailable, motivation to procure METH, extinction responding, and the modulation of cued reinstatement by 5-HT2CR manipulation. Aim 2 will determine the impact of METH self-administration on cognitive flexibility and assess a mechanism - altered 5- HT2CRs in the orbitofrontal cortex - through which the observed deficits may manifest. Fulfillment of the training goals, which include acquisition of a diverse skill set i foundational neurobiological techniques and professional development in the field of addiction neuroscience, will be attained through a combination of coursework and readings, hands-on training with individuals who have expertise in the proposed techniques, attendance at workshops, seminars, and national conferences, and monthly meetings with the training team. The results of the proposed research will move the field toward a clearer understanding of the antecedents and consequences of drug use that confer enhanced addiction vulnerability in at-risk populations. The results of the proposed experiments could be used to facilitate development of individualized prevention and treatment strategies for females and adolescent users, who are at heightened risk to transition to dependence.