Adolescent social stress, cortical dopamine and drug susceptibility

描述（由申请人提供）：青少年社会压力暴露与精神和药物滥用障碍的发生率较高有关，但尚不清楚青少年社会压力如何改变神经机制以导致精神病理。我们已经开发了一个青少年社会失败的老鼠模型，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源之一。成年后，先前被打败的大鼠表现出内侧前额叶皮层（mPFC）多巴胺（DA）组织含量下降，安非他明诱发的细胞外mPFC DA释放受到抑制。先前暴露于青少年社会失败的成年大鼠对安非他明也表现出增加的行为反应，包括更大的安非他明引起的运动和对安非他明相关线索的更高偏好。在这个提议中，我们将检验青少年失败暴露后mPFC DA功能低下导致成年期安非他明敏感性升高的假设。我们还将测试是否可以通过不同时间点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的活性。该动物模型的新应用为首次建立青少年压力、mPFC DA功能和增强药物滥用敏感性之间的直接联系提供了一种创新手段。该研究将为开发药物治疗策略以治疗青少年受欺凌压力导致的成瘾障碍提供重要信息。积极的研究结果也将确定mPFC DA系统是青少年压力诱发的行为功能障碍的重要中介。鉴于mPFC在认知和自上而下的情绪调节中的关键作用，这在指导青少年压力导致的障碍的潜在治疗方面具有广泛的应用。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学生的研究经验。这些研究将为学生提供有意义和高质量的神经生物学、神经药理学和行为神经科学方面的早期培训机会，在一个联邦资助的科学研究方面代表性不足的农村州。最终结果将增强USD的研究培训环境，并增加来自南达科他州的学生在健康科学领域追求未来职业的前景。

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.