DREADD Manipulations of Drug Choice

药物选择的可怕操纵

• 批准号: 10574862
• 负责人: Hannah Robinson
• 金额: $ 5.27万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574862
• 关键词: Agonist; Amphetamines; Animals; Basal Ganglia; Cardiovascular system; Chronic; Clinical Data; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine use disorder; Data; Development; Disease; Dopamine; Dose; Drug Modulation; Effectiveness; Extinction; Female; Fiber; Food; Genetic; Health; Human; Ligands; Maintenance; Measures; Mediating; Methods; Microdialysis; Neurobiology; Neurosciences Research; Neurotransmitters; Norepinephrine; Nucleus Accumbens; Osmosis; Overdose; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Photometry; Play; Procedures; Psychological reinforcement; Public Health; Publishing; Pump; Rattus; Recovery; Research Support; Role; Sprague-Dawley Rats; Stimulant; Synapses; Testing; Training; Transgenic Organisms; Twin Multiple Birth; United States; United States Food and Drug Administration; Ventral Tegmental Area; Viral; Virus Diseases; abuse liability; awake; career development; cocaine self-administration; designer receptors exclusively activated by designer drugs; dopamine transporter; drug seeking behavior; effective therapy; improved; in vivo; inhibitor; innovation; male; neurochemistry; neurotransmission; neurotransmitter release; noradrenaline transporter; novel; opioid use disorder; pre-clinical research; pre-doctoral; reinforced behavior; serotonin transporter; small molecule; theories; tool; treatment effect

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.

项目摘要 在美国和全世界，可卡因滥用和上瘾仍然是一个长期存在的健康问题。那里 目前还没有食品和药物管理局批准的治疗可卡因使用障碍的药物疗法。 安非他明的维护已显示出作为治疗可卡因滥用的有效方法的前景，但滥用责任 而对心血管的担忧使其不太可能被批准作为一种治疗方案。此外，该机制 安非他明在这方面的作用尚不清楚；然而，安非他明的维持 抑制可卡因诱导的伏隔核(NAC)多巴胺的增加。这项提议将 确定皮质边缘多巴胺通路和多巴胺紧张度在调节可卡因中的作用 强化和可卡因诱导的中脑边缘多巴胺增加。这个项目的前提是 大脑皮质边缘VTA多巴胺通路在药物寻找行为的调节中起着重要作用。 目的1确定VTA中刺激性DREADDS对可卡因选择的影响。男性和女性TH：CRE 转基因SD大鼠将被病毒感染DREADDS，并接受可卡因和食物选择的训练 程序。将通过渗透压泵长期给动物注射DREADD激动剂以激活DREADDS 并确定它们对可卡因选择的影响。目标2将确定刺激和刺激的神经化学效应 抑制DREADD单独激活和可卡因诱导的NAC多巴胺增加。跟随 从DREADDS病毒感染中恢复后，动物将反复服用DREADD激动剂。基本的 NAC多巴胺水平和可卡因注射后多巴胺能张力的变化将通过以下方法测量 体内纤维光度法(例如dLight)。总体而言，这项建议将有助于提高对 加强和引导开发更有效的可卡因使用障碍治疗方法。