Adolescent social stress, cortical dopamine and drug susceptibility

描述（由申请人提供）：青少年暴露于社会压力与精神病和药物滥用障碍的发生率较高相关，但尚不清楚青少年社会压力如何改变神经机制，从而导致精神病理学。我们开发了一种青少年社交失败的大鼠模型，以调查青少年欺凌的有害影响，这是全世界人类经历的最常见的社会压力之一。作为成年人，以前失败的大鼠表现出减少内侧前额叶皮层（mPFC）多巴胺（DA）组织含量和抑制安非他明诱发的细胞外mPFC DA释放。以前暴露于青少年社会失败的成年大鼠也表现出对苯丙胺的行为反应增加，包括更大的苯丙胺诱导的运动和对苯丙胺相关线索的更高偏好。在这项建议中，我们将测试的假设，mPFC DA功能减退后，青少年失败的曝光导致提高安非他明的敏感性在成年期。我们还将测试是否可以通过在不同时间点提供的药理学操作来预防青少年社会压力后安非他明敏感性的增加：（1）在青少年压力经历期间阻断对mPFC DA的破坏，或（2）在压力暴露后恢复mPFC DA活性。新的使用这种动物模型来研究这些问题提供了一种创新的手段，首次建立了青少年压力，mPFC DA功能和滥用药物的敏感性增强之间的直接联系。这项拟议的研究将为开发治疗青少年因遭受欺凌压力而导致的成瘾性疾病的药物治疗策略提供重要信息。积极的研究结果也将确定mPFC DA系统作为一个重要的调解人的青少年压力引起的行为功能障碍。鉴于mPFC在认知和自上而下的情绪调节中的关键作用，这对于指导青少年压力导致的成瘾以外的疾病的潜在治疗具有广泛的应用。除了解决一个重要的科学问题外，目前的提案还将丰富南达科他州大学的学生研究经验。这些研究将为学生提供有意义的和高质量的早期培训机会，在神经生物学，神经药理学和行为神经科学在一个农村国家是代表性不足的联邦资助的科学研究。最终的结果将加强在USD的研究培训环境，并增加来自南达科他州的学生在健康相关科学追求未来的职业生涯的前景。

DESCRIPTION (provided by applicant): Adolescent exposure to social stress is associated with a greater incidence of psychiatric and substance abuse disorders, but it is not known how neural mechanisms are altered by adolescent social stress to result in psychopathologies. We have developed a rat model of adolescent social defeat to investigate detrimental effects of teenage bullying, one of the most common social stressors experienced by humans worldwide. As adults, previously defeated rats exhibit decreased medial prefrontal cortex (mPFC) dopamine (DA) tissue content and dampened amphetamine-evoked extracellular mPFC DA release. Adult rats previously exposed to adolescent social defeat also show increased behavioral responses to amphetamine, including greater amphetamine-induced locomotion and a higher preference for amphetamine-associated cues. In this proposal, we will test the hypothesis that mPFC DA hypofunction following adolescent defeat exposure causes heightened amphetamine sensitivity in adulthood. We will also test whether increased amphetamine sensitivity following adolescent social stress can be prevented through pharmacological manipulations delivered at different time points: either (1) by blocking disruption to mPFC DA during the adolescent stress experience, or (2) by restoring mPFC DA activity after stress exposure. The novel use of this animal model to examine these questions provides an innovative means of establishing for the first time a direct link between adolescent stress, mPFC DA function and enhanced sensitivity to drugs of abuse. The proposed research will provide important information for the development of pharmacotherapeutic strategies for treating addiction disorders resulting from exposure to bullying stress in adolescence. Positive findings will also identify the mPFC DA system as an important mediator of adolescent stress-induced behavioral dysfunction. Given the pivotal role of the mPFC in cognition and top-down regulation of emotion, this has broad application for directing potential therapies for disorders that result from adolescent stress beyond addiction. In addition to addressing an important scientific problem, the current proposal will also enrich student research experiences at the University of South Dakota. These studies will provide students with meaningful and high quality early training opportunities in neurobiology, neuropharmacology and behavioral neuroscience in a rural state that is under- represented in terms of federally funded scientific research. The end result will enhance the research training environment at USD and increase the prospects for students from South Dakota to pursue a future career in health-related sciences.