Mechanisms of psychostimulant-sleep interactions

Utah State Higher Education System--University Of Utah, Salt Lake City UT

Investigators

Abstract

––– PROJECT SUMMARY/ABSTRACT –––––––––––––––––––– R01: Psychostimulant responses and sleep. –––– Substance use disorder (SUD) and sleep alterations are reciprocally connected in a vicious feed forward cycle. In one direction, repeated exposure to addictive substances affects sleep timing, duration, and quality. The effects of drugs on sleep can even last into the abstinence period, during which patients experience irregular sleep and insomnia, and this persistent sleep disturbance is a strong risk factor for relapse to drug use. Conversely, sleep disturbances cause stress and mood imbalance and are a risk factor for the development of SUD. This includes sleep disturbances caused by means other than drugs of abuse, such as shiftwork. Some neurobiological systems are known to influence sleep as well as motivation and reward. These systems are often targeted by drugs of abuse, and a substantial body of literature has focused on the disruptive effects of acute exposure to substance of abuse on sleep. However, mechanistic studies of long-term sleep irregularities after drug exposure, as well as of how sleep disturbances affect SUD-related behaviors remain scarce. This application responds to the one-time RFA-DA-25-045 “Mechanistic studies to investigate the interrelationship between sleep and/or circadian rhythms and substance use disorders”. The goal of this proposal is to identify genes and molecular mechanisms that affect psychostimulant-induced sleep irregularities as well as sleep deprivation-caused changes in experience-dependent amphetamine preference (EDAP). We will do so using the vinegar fly, Drosophila melanogaster, an established genetic model organism with considerable economy of scale and excellent experimental amenability. Based on preliminary data showing that recovery from acute amphetamine exposure, which suppresses sleep, leads to sleep rebound, we propose to 1) determine mechanisms of stimulant-induced sleep changes, including anatomical as well as genetic investigations. 2) We will use within-fly amphetamine exposure to screen Drosophila orthologs of 2 094 human brain-enriched transcripts for their role in psychostimulant-induced sleep changes. Lastly, we have recently developed a self- administration assay that monitors EDAP with high temporal resolution, where flies develop preference for amphetamine within ~12 h, starting from indifference or slight aversion. EDAP depends on Drosophila’s canonical dopaminergic ‘reward system’. Our preliminary data show that mechanical sleep deprivation accelerates the development of EDAP and promotes EDAP at lower, normally sub-threshold amphetamine concentrations, as observed in mammals. We will 3) determine circuit and genetic mechanisms of sleep deprivation-induced changes in amphetamine preference. Results from these investigations will offer RFA- relevant “insights into the fundamental processes that link SUDs to disorders of sleep…and vice-versa”.