Identifying patterns of human polysubstance use to guide development of rodent models

项目摘要（补充） 这个建议是为博士生哈维尔梅萨的多样性补充。这种补充剂可以让哈维尔， 谁是一个代表性不足的少数民族在生物医学科学，根据家长补助金DA045140工作。 在补充期间，哈维尔将接受神经科学前沿技术的培训， 扩展他在药物寻求的转化啮齿动物模型方面的概念知识。指导团队是 由父母补助金的MPI，洛里Knackstedt和琳达Cottler博士，以及共同I的Marek博士组成 施温特和巴里塞特洛。此外，贾维尔的论文委员会成员杰西·达勒里博士将 有助于指导。所有导师都是现任或前任NIDA受助人，并拥有从使用 临床前啮齿动物模型的药物寻求，以揭示神经生物学的变化（博士Knackstedt，施温特 和Setlow）评估人类吸毒模式（Cottler博士），并使用行为策略来减少 Dallery博士（Dr. Dallery）哈维尔将有助于数据收集家长补助金的目标，同时也追求他的 他所建立的独立目标。父母补助金的目的是反向翻译人类的 可卡因-酒精和可卡因-大麻多种物质使用（PSU）的啮齿动物模型。其中一种模式是 在Knackstedt实验室中使用，有两篇出版物发现，可卡因和 酒精导致独特的NA核心谷氨酸适应，不同于单独的可卡因自我给药。 具体来说，我们发现，在可卡因和线索+可卡因引发的恢复测试中，NA核心 单独服用可卡因的大鼠谷氨酸流出增加，但在那些有连续服用可卡因史的大鼠中没有增加。 可卡因和酒精消费，尽管在恢复测试期间可卡因寻求水平相当。 这种谷氨酸外流驱动可卡因寻求的恢复，因为NA核心谷氨酸受体的阻断， 削弱这种恢复。我们还发现，减少恢复诱导的Fos表达在NA 核心和PFC发生在PSU组相对于可卡因组，与以下观点一致， PFC-NA核心通路不介导PSU条件下可卡因寻求的恢复。相反，我们 观察到可卡因-酒精PSU大鼠的BLA中Fos表达相对于仅可卡因大鼠增加。在这里， 哈维尔建议使用这种可卡因+酒精连续消费的模型来研究小说 在PSU模型中可卡因寻求复发的神经回路。他的目标是测试 假设1）BLA的失活将抑制PSU大鼠中可卡因寻求的恢复， 可能在更大程度上比可卡因只大鼠;和2）PFC-NA核心途径的失活将 抑制仅自我施用可卡因的大鼠而不是PSU大鼠中可卡因寻求的恢复。 这些目标将提供关于不同与重叠神经回路存在的有价值的信息 在可卡因单一物质使用与可卡因-酒精多物质使用中介导可卡因寻求。

Project Summary (Supplement) This proposal is for a Diversity Supplement for a PhD student, Javier Mesa. This supplement will allow Javier, who is an underrepresented minority in the biomedical sciences, to work under the parent grant DA045140. During the course of the supplement, Javier will be trained on cutting-edge techniques in neuroscience and expand his conceptual knowledge on translational rodent models of drug seeking. The mentoring team is composed of the MPIs of the parent grant, Drs. Lori Knackstedt and Linda Cottler, and co-I’s Drs. Marek Schwendt and Barry Setlow. Additionally, Dr. Jesse Dallery, a member of Javier’s dissertation committee, will contribute to mentoring. All mentors are current or past NIDA grantees, and have expertise ranging from the use of preclinical rodent models of drug-seeking to uncover neurobiological changes (Drs. Knackstedt, Schwendt and Setlow) to assessing human patterns of drug-taking (Dr. Cottler) and using behavioral strategies to reduce drug seeking (Dr. Dallery). Javier will contribute to data collection for parent grant aims, while also pursuing his own independent aims that he has constructed. The parent grant aims to back-translate human patterns of cocaine-alcohol and cocaine-cannabis polysubstance use (PSU) into rodent models. One such model has been in use in the Knackstedt lab, with two publications finding that sequential self-administration of cocaine and alcohol leads to unique NA core glutamate adaptations differing from that of cocaine self-administration alone. Specifically, we found that during a both a cocaine- and a cue+cocaine-primed reinstatement test, NA core glutamate efflux increases in rats that consumed cocaine alone, but not in those with a history of sequential cocaine and alcohol consumption, despite equivalent levels of cocaine-seeking during the reinstatement test. This glutamate efflux drives the reinstatement of cocaine-seeking, as blockade of NA core glutamate receptors attenuates such reinstatement. We also found that reduced reinstatement-induced Fos expression in the NA core and the PFC occurred in the PSU group relative to the cocaine-only group, consistent with the idea that PFC-NA core pathways do not mediate reinstatement of cocaine seeking in the PSU condition. Conversely, we observed increased Fos expression in the BLA of cocaine-alcohol PSU rats relative to cocaine-only rats. Here, Javier proposes to use this model of sequential cocaine+alcohol consumption to investigate the novel neurocircuitry underlying relapse to cocaine seeking in the PSU model. His aims are designed to test the hypotheses that 1) inactivation of the BLA will suppress the reinstatement of cocaine seeking in rats in PSU rats, possibly to a greater extent than in cocaine-only rats; and 2) inactivation of the PFC-NA core pathway will suppress the reinstatement of cocaine seeking in rats that self-administered only cocaine and not in PSU rats. These aims will provide valuable information regarding the presence of distinct vs. overlapping neurocircuitries mediating cocaine seeking in cocaine monosubstance use vs. cocaine-alcohol polysubstance use.