DREADD Manipulations of Drug Choice

项目摘要 可卡因滥用和成瘾在美国和世界范围内仍然是一个持续存在的健康问题。那里 目前没有食品和药物管理局批准的可卡因使用障碍的药物疗法。 安非他明维持治疗已显示出作为可卡因滥用的有效治疗的希望，但滥用责任 以及心血管方面的问题使得它不太可能被批准作为一种治疗选择。此外，该机制 安非他明在这种情况下的作用是未知的;然而，安非他明的维持一直是 研究表明，它可以减弱可卡因诱导的伏隔核（NAc）多巴胺的增加。这项建议会 确定中脑皮质边缘多巴胺通路和多巴胺张力在调节可卡因中的作用 加强和可卡因诱导的中脑边缘多巴胺增加。这个项目的前提是， 中脑皮质边缘VTA多巴胺通路在药物觅药行为的调节中起重要作用。 目的1将确定VTA中刺激性DREADD对可卡因选择的影响。男性和女性TH：Cre 转基因Sprague-Dawley大鼠将被DREADD病毒感染，并接受可卡因与食物选择的训练 procedure.将通过渗透泵长期给予动物DREADD激动剂以激活DREADD 并确定它们对可卡因选择的影响。目的2将确定刺激和 抑制DREADD激活单独和可卡因诱导的NAc多巴胺增加。以下 当动物从DREADD的病毒感染中恢复时，将重复给予DREADD激动剂。基底 NAc多巴胺水平和可卡因给药后多巴胺能紧张性的变化将通过 体内纤维光度法（例如dLight）。总体而言，该提案将有助于提高对 可卡因强化作用并指导开发更有效的可卡因使用障碍治疗方法。

Project Summary Cocaine abuse and addiction remain a persistent health problem both in the United States and worldwide. There are currently no Food and Drug administration-approved pharmacotherapies for cocaine use disorder. Amphetamine maintenance has shown promise as an effective treatment for cocaine abuse, but abuse liability and cardiovascular concerns make it unlikely to be approved as a treatment option. Additionally, the mechanism by which amphetamine functions in this context is unknown; however, amphetamine maintenance has been shown to blunt cocaine-induced dopamine increases in the nucleus accumbens (NAc). This proposal will determine the role of mesocorticolimbic dopamine pathway and dopamine tone in modulating cocaine reinforcement and cocaine-induced increases in mesolimbic dopamine. The premise of this project is that the mesocorticolimbic VTA dopamine pathway plays a significant role in the modulation of drug seeking behavior. Aim 1 will determine the effects of stimulatory DREADDs in the VTA on cocaine choice. Male and female TH:Cre transgenic Sprague-Dawley rats will be virally infected with DREADDs and trained on a cocaine-vs-food choice procedure. Animals will be chronically administered a DREADD agonist via osmotic pump to activate DREADDs and determine their effect on cocaine choice. Aim 2 will determine the neurochemical effects of stimulatory and inhibitory DREADD activation both alone and on cocaine-induced increases in NAc dopamine. Following recovery from viral infection of DREADDs, animals will be repeatedly administered a DREADD agonist. Basal NAc dopamine levels and changes in dopaminergic tone following cocaine administration will be measured via in vivo fiber photometry (e.g. dLight). Overall, this proposal will help improve mechanistic understanding of cocaine reinforcement and guide development of more effective cocaine use disorder treatments.