Adolescent social stress, cortical dopamine and drug susceptibility

青少年社会压力、皮质多巴胺和药物敏感性

• 批准号: 8688582
• 负责人: MICHAEL JAMES WATT
• 金额: $ 42.3万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688582
• 关键词: Address; Adolescence; Adolescent; Adult; Affect; Aggressive behavior; Amphetamines; Animal Model; Behavior; Behavioral; Behavioral Assay; Brain; Brain region; Childhood; Clinical; Clinical Research; Cognition; Cues; Development; Disease; Dopamine; Dopaminergic Agents; Down-Regulation; Drug usage; Elderly; Emotions; Environment; Exhibits; Exposure to; Functional disorder; Funding; Future; Goals; Health; High Pressure Liquid Chromatography; Human; Incidence; Intervention; Link; Locomotion; Long-Term Effects; Measurement; Measures; Medial; Mediating; Mediator of activation protein; Microdialysis; Modeling; Neurobiology; Neuropharmacology; Neurosciences; Pharmaceutical Preparations; Pharmacotherapy; Predisposition; Prefrontal Cortex; Psychopathology; Rattus; Recording of previous events; Relative (related person); Research; Research Training; Rest; Role; Rural; Science; South Dakota; Stress; Students; Substance Use Disorder; Substance abuse problem; Testing; Time; Tissues; Training; Universities; addiction; bullying; career; direct application; dopamine system; drug of abuse; drug sensitivity; effective intervention; experience; extracellular; in vivo; innovation; neurochemistry; neuromechanism; novel; preclinical study; preference; prevent; public health relevance; research study; response; social; social stress; stressor; transmission process

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.

描述（由申请人提供）：青少年接触社会压力与精神病和药物滥用障碍的发生率更大有关，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。我们已经开发了一种青少年社会失败的大鼠模型，以调查青少年欺凌的有害影响，这是全世界人类最常见的社会压力之一。作为成年人，先前击败的大鼠表现出降低的内侧前额叶皮层（MPFC）多巴胺（DA）组织含量，并抑制了苯丙胺诱发的细胞外MPFC DA释放。先前接触青少年社会失败的成年大鼠还显示出对苯丙胺的行为反应增加，包括苯丙胺诱导的运动和对苯丙胺相关线索的偏爱更高。在此提案中，我们将检验以下假设：青春期失败暴露后MPFC DA功能障碍会导致成年后的苯丙胺敏感性提高。我们还将测试是否可以通过在不同时间点传递的药理学操作来预防青少年社会压力后提高的苯丙胺敏感性：（1）是否通过在青少年压力体验期间阻止对MPFC DA的破坏，或（2）通过恢复压力暴露后的MPFC DA活性来恢复MPFC DA。该动物模型检查这些问题的新颖使用提供了一种创新的手段，以首次建立青少年应力，MPFC DA功能和增强对滥用药物的敏感性之间的直接联系。拟议的研究将提供重要信息，以开发药物治疗策略，以治疗青春期暴露于欺凌压力而导致的成瘾疾病。积极的发现还将确定MPFC DA系统是青少年应力诱导的行为功能障碍的重要介体。鉴于MPFC在认知和自上而下的情绪调节中的关键作用，这在指导潜在的疗法的疾病中，这些疾病是由于青少年压力而超出成瘾的疾病。除了解决一个重要的科学问题外，当前的建议还将丰富南达科他大学的学生研究经验。这些研究将为学生提供有意义，高质量的早期培训机会，以在农村国家的神经生物学，神经药理和行为神经科学领域为以联邦资助的科学研究为代表。最终结果将增强美元的研究培训环境，并增加南达科他州的学生从事与健康有关的科学领域的未来职业的前景。