Oxytocin projections mediate social and drug reward

项目总结

Project Summary Substance use disorder (SUD) is prevalent in the US with over 10% of adults fitting the criteria for diagnosis. Unfortunately, SUD treatments are often unsuccessful, with up to 75% of patients experiencing relapse. SUD is associated with problematic reward processing, leading to drug use at the expense of natural rewards and despite negative consequences. Addiction recovery programs often require drug abstinence while reinforcing engagement with natural rewards such as socialization. Research suggests that oxytocin administration could help with this process and improve treatment outcomes for SUD. Although the therapeutic potential of oxytocin is already being investigated in clinical trials with encouraging outcomes, the effects of oxytocin on reward- related neural circuits are not understood. Most studies point to oxytocin decreasing the reinforcing effects of drugs but increasing the salience of social stimuli. The detection of rewarding stimuli is regulated in part by the mesolimbic dopamine system, with dopaminergic cell bodies in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc). Emerging evidence suggests that different circuits facilitate drug versus social reward, with drug reward depending on phasic (fast bursts) dopamine release and social reward on tonic (slow, steady) dopamine release in the NAc. Oxytocin’s therapeutic effects for addiction may be a result of oxytocin shifting dopamine release patterns from phasic to tonic, thus rebalancing the pathways facilitating drug and social reward. The current proposal will assess the role of oxytocin projections and oxytocin receptors located in reward-related brain regions on preference for drug vs social reward and phasic vs tonic dopamine release. The proposed study will be the first to systematically investigate the neural pathways and receptor sites utilized by oxytocin to mediate reward processing. The proposed study incorporates contemporary techniques for manipulating neural circuits (DREADD and CRISPR/Cas9 technologies) and inventive twists on conditioned place preference testing and in vivo dopamine quantification. Clarifying the mechanisms by which oxytocin mediates drug and social reward is crucial for harnessing the full therapeutical potential of oxytocin for SUD.