Effects of oxycodone self‐administration on sleep duration and quality in male and female rats

Abstract

Many symptoms associated with opioid withdrawal contribute to continued used and relapse. Long‐lasting sleep disturbances are common symptoms of opioid use and withdrawal, contributing to high rates of relapse. Thus, reducing sleep impairments during abstinence may be a novel and effective treatment approach for opioid use disorder. Understanding the acute and long‐term effects of opioid exposure on sleep is critical, yet understudied in animal models of opioid use disorder (OUD). Although oxycodone is widely used medically and recreationally, no study to date has assessed progressive changes in sleep/wake architecture following oxycodone self‐administration in animals. In the present studies, male (n=12) and female (n=6) Sprague Dawley rats were implanted with both electroencephalography (EEG) recording devices and intravenous jugular catheters to monitor sleep duration and quality prior to and following oxycodone self‐administration. Rats were first trained to self‐administer sucrose pellets on a fixed ratio 3 (FR3) schedule of reinforcement during the first 2 hours of the dark cycle. Next, half of the rats continued to self‐administer sucrose pellets, while the other half self‐administered oxycodone (0.1 mg/kg/inf) for 30 days. Rats then underwent 20 days of extinction where the reinforcer and light cues were absent and responding had no scheduled consequences. EEG recordings were collected on the last day of sucrose pellet self‐administration and every 5th day of oxycodone self‐administration or abstinence. EEGs were recorded from each rats’ homecage, following completion of each self‐administration session and lasted for 21 hours. EEG data were analyzed using Neuroscore software, each 10s epoch was manually scored as wake, rapid eye movement (REM) sleep, non‐REM (NREM) sleep. Sleep and quantitative EEG were examined using within‐subject changes from a drug‐free baseline as well as between‐subject changes (oxycodone vs sucrose pellet self‐administration) using custom Matlab scripts and GraphPad prism. On average, rats self‐administered 2.6 mg/kg oxycodone per 2‐hr session, with considerable variability in overall intake (0.8‐5mg/kg per day). Preliminary analysis suggests subtle alterations in sleep duration across the self‐administration period. Specifically, acute increases in time awake were present within the first 3 hours following self‐administration, yet dissipated across the 30 day self‐administration period. Group effects on sleep duration during abstinence were not found. State‐dependent spectral analysis is still ongoing, but preliminary data suggest sleep quality (e.g. delta power during non‐REM sleep) is reduced during the initial week of self‐administration and rebounds during abstinence. Correlative analyses between intake and sleep measures are still ongoing. Understanding the direct and long‐lasting pharmacological effects of oxycodone self‐administration on sleep will be beneficial to examine novel pharmacotherapies to ameliorate sleep disturbances associated with OUD.