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

描述（由申请人提供）：青春期是儿童和成年之间的过渡时期，大多数药物使用开始于此期间。与男性相比，在青春期开始使用药物的女性与较差的长期结果有关，例如认知缺陷增加和过渡到依赖的可能性。为了解决我们在可能增强青少年和女性成瘾脆弱性的机制方面的知识差距，重要的是要了解脆弱人群（例如青少年和女性）的典型药物寻求模式以及持久的药物诱导的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，可能会加剧脆弱性的药物依赖性在吸毒发作和女性甲基苯丙胺（METH）用户。实验将采用行为，药理学和免疫组织化学技术在大鼠模型中评估两个特定的目标。目的1将描述年龄和性别特异性模式的适应不良的药物寻求和调查的机制，提高复发的检查方面的静脉内METH自我管理，如响应时METH是不可用的，动机，采购METH，灭绝响应，和调制的线索恢复5-HT2CR操作。目标2将确定METH自我给药对认知灵活性的影响，并评估一种机制-眶额皮质中5-HT2CRs的改变-通过该机制，观察到的缺陷可能会显现。培训目标的实现，其中包括在成瘾神经科学领域的基础神经生物学技术和专业发展的多样化技能集的收购，将通过课程和阅读的组合，与具有所提出的技术专业知识的个人进行实践培训，参加研讨会，研讨会和全国会议，以及与培训团队的每月会议来实现。拟议研究的结果将使该领域更清楚地了解药物使用的前因和后果，从而增强高危人群的成瘾脆弱性。拟议实验的结果可用于促进制定针对女性和青少年吸毒者的个性化预防和治疗策略，这些人过渡到依赖的风险很高。

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.