Effects of Non‐contingent and Self‐administered Oxycodone on Sleep Architecture in Rats

Abstract

Opioid use disorder (OUD) is an ongoing global public health concern. Opioid analgesics such as oxycodone are major contributors to this epidemic because of their abuse potential. Thus, understanding acute and long-term effects of opioid exposure is critical. Sleep disturbances are commonly reported yet understudied symptoms of OUD commonly associated with relapse. Normalizing the sleep disturbances associated with OUD could be a novel therapeutic approach for relapse prevention. No study to date has assessed progressive changes in sleep/wake architecture following contingent or non-contingent oxycodone exposure in animals. In the present studies, effects of oxycodone on sleep/wake architecture and quantitative electroencephalography (EEG) were examined in freely moving, Sprague-Dawley rats implanted with EEG surface electrodes and wireless transmitters. 24 hr EEG home cage recordings were scored manually as wake, rapid eye movement (REM) and non-REM (NREM) sleep. In one cohort, effects of acute, noncontingent oxycodone (1-3 mg/kg; sc) were examined when administered 2 hr into the light cycle. Oxycodone dose-dependently increased time awake and reduced NREM and REM sleep duration. Spectral power analysis showed that oxycodone dose-dependently increased high frequency gamma power (50-100Hz). In a second cohort, rats were implanted with both EEG implants and intravenous jugular catheters to examine effects of oxycodone self-administration (SA) on sleep. Rats were 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, rats were divided into two groups; half continued to self-administer sucrose pellets, while the other self-administered oxycodone (0.056 mg/kg/inf for 7 days; then 0.1 mg/kg/inf for 10 days). On average, rats self-administered 1.04 mg/kg oxycodone per 2-hr session. Rats then underwent response extinction for 5 days where the reinforcer and light cues were absent followed by a single light-cue elicited reinstatement session. EEG was recorded from the home cages for the remaining 22 hours per day. Preliminary data suggest that, compared to the last day of sucrose pellet SA, oxycodone SA increased time awake and decreased NREM and REM sleep. These changes were not seen in rats self-administering sucrose pellets. The increase in wake duration persisted throughout oxycodone SA sessions, but the reduction in REM sleep dissipated over time. Ongoing analyses are examining sleep during abstinence to determine whether abstinence-related changes in sleep occur in a similar manner to other illicit drug classes. The effects of noncontingent oxycodone are more prominent than self-administered despite similar total daily intake. Self-administration paradigms yielding higher daily intake may be necessary to engender greater sleep disturbances. Although preliminary, understanding the direct pharmacological effects of oxycodone self-administration on sleep will be beneficial to examine potential novel pharmacotherapies to normalize sleep disturbances associated with OUD.