Natalie Zlebnik - US grants

DESCRIPTION (provided by applicant): Relapse to drug abuse is the single greatest problem in addiction treatment. Experimental evidence in humans and animals suggests that females are more prone to relapse than males, identifying a need for sex-specific treatment strategies for drug abuse. Aerobic exercise has emerged as an effective behavioral treatment for addiction, and studies suggest that it might be more effective to decrease drug abuse in females than males. The long-term goal of this project is to characterize exercise as a treatment for addiction in both males and females. The current aims are to examine the effects of aerobic exercise in male and female rats on relapse after a prolonged abstinence from drug use; determine whether exercise will reduce relapse-related neuroadaptations in brain areas important for addiction; and investigate differential effects of exercise in females vs. males. It is hypothesized that exercise will diminish relapse after prolonged abstinence, reverse or eliminate brain adaptations associated with prolonged abstinence, and act more effectively in females than in males. The experiments are designed to test the effects of voluntary wheel running in rats that are in prolonged withdrawal from intravenous cocaine self-administration, and the training potential of this project is to provide instruction in cellular and molecular experimental techniques paired with behavioral paradigms. To this end, behavioral measures, protein analysis, and neuronal morphology will be assessed. The proposed experiments have the potential to elucidate a novel sex-specific treatment for relapse and will give insight into the neurobiological mechanism of its action.

PROJECT SUMMARY Relapse to drug abuse is the single greatest challenge in addiction treatment. Relapse can occur even after prolonged abstinence and is often preceded by robust drug craving precipitated by exposure to drug-paired stimuli and environments. Aerobic exercise is a novel and promising behavioral treatment for drug addiction and relapse. However, the precise mechanism of its therapeutic effects is unknown. The long-term goal of this project is to characterize the striatal network dynamics that mediate the effects of exercise on addiction and relapse. The current aims of this proposal are to examine the impact of chronic wheel running on rapid subsecond dopamine release dynamics and dopamine terminal function as well as on the longitudinal development of phasic dopamine signals that promote cocaine-seeking behavior and on the recruitment of cell- type specific neural processing of cocaine seeking and cocaine-paired cues. It is hypothesized that chronic wheel running will (1) attenuate cocaine-evoked subsecond dopamine release in the striatum, (2) decrease striatal phasic dopaminergic signals accompanying cocaine-paired cues and cocaine seeking, and (3) attenuate D1-MSN and potentiate D2-MSN encoding of cocaine-paired cues and cocaine seeking. These experiments will employ a sophisticated mouse model of cocaine relapse, state-of-the-art in vivo fast-scan cyclic voltammetry recordings, in vivo multiple single-unit electrophysiological recordings, and chemogenetic and optogenetic technologies to examine these questions in behaving animals. The proposed experiments aim to increase our understanding of the neurobiological substrates that mediate drug craving and relapse and identify the neurochemical and neurophysiological mechanisms of the beneficial effects of exercise.