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.

项目概要 可卡因滥用和成瘾仍然是美国和全世界持续存在的健康问题。那里 目前尚无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。 安非他明维持治疗已显示出作为可卡因滥用的有效治疗方法的前景，但滥用的可能性 心血管问题使其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尚不清楚；然而，安非他明维持治疗已 被证明可以抑制可卡因诱导的伏隔核（NAc）中多巴胺的增加。该提案将 确定中皮质边缘多巴胺通路和多巴胺音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。该项目的前提是 中皮质边缘 VTA 多巴胺通路在药物寻求行为的调节中发挥着重要作用。 目标 1 将确定 VTA 中的刺激性 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 程序。动物将通过渗透泵长期服用 DREADD 激动剂以激活 DREADD 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作用 单独和可卡因诱导的 NAc 多巴胺增加均抑制 DREADD 激活。下列的 从 DREADD 病毒感染中恢复后，动物将被重复施用 DREADD 激动剂。基础 NAc 多巴胺水平和可卡因给药后多巴胺能音调的变化将通过以下方式测量 体内光纤光度测定（例如 dLight）。总体而言，该提案将有助于提高对机制的理解 可卡因强化并指导开发更有效的可卡因使用障碍治疗方法。