DREADD Manipulations of Drug Choice

点击翻译按钮获取中文摘要

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.