Insomnia treatment drug lemborexant rescues REM sleep dysfunction associated with methamphetamine vapor withdrawal

Authors' Affiliations

Marissa Jones, College of Biomedical Sciences, East Tennessee State University, Johnson City, TN

Location

D.P. Culp Center Ballroom

Start Date

4-5-2024 9:00 AM

End Date

4-5-2024 11:30 AM

Poster Number

146

Name of Project's Faculty Sponsor

Brooke Schmeichel

Faculty Sponsor's Department

Biomedical Sciences

Classification of First Author

Graduate Student-Doctoral

Competition Type

Competitive

Type

Poster Presentation

Presentation Category

Science, Technology and Engineering

Abstract or Artist's Statement

Insomnia treatment drug lemborexant rescues REM sleep dysfunction associated with methamphetamine vapor withdrawal Huffcutt, Galen P., Jones, Marissa R. and Schmeichel, Brooke E.  Biomedical Sciences Department, Quillen College of Medicine, East Tennessee State University, Johnson City, TN USA In 2021, 2.5 million people abused the psychostimulant drug methamphetamine (MA) in the U.S. Chronic MA use can lead to disordered sleep, particularly during withdrawal, and clinical studies show that sleep dysfunction is a strong predictor for relapse. The neuropeptide hypocretin (HCRT) plays a critical role in the transition from sleep to wakefulness and also modulates drug reward. Enhanced HCRT signaling in the brain underlies the sleep disorder insomnia and the dual-HCRT-receptor antagonist lemborexant (LEM) is prescribed for treatment of insomnia in humans. Here we characterized sleep dysfunction associated with MA vapor (MAV) withdrawal in rats and hypothesized that HCRT signaling contributes to poor sleep. Adult Wistar rats (N=15, 8M/7F) received a telemetry device implant and EEG/EMG signals were recorded for 23 hours (12h light:11 h dark). Rats were exposed to passive MAV for 4 weeks to induce dependence. Rats showed significant increases in maximum body temperature and decreases in novel object recognition during drug withdrawal. Sleep/wake data were analyzed prior to MAV exposure (baseline; BL), during withdrawal (1 week of MAV abstinence), and during protracted abstinence (four weeks of MAV abstinence). LEM (0 and 30 mg/kg, counter-balanced) was administered at the beginning of the light cycle immediately prior to 1-week, and 4-week sleep recordings. After 1 week of abstinence, rats showed a decrease in rapid eye movement (REM) sleep time in the light cycle during withdrawal, while LEM restored this REM sleep. There was also an increase in REM sleep time in males during the dark cycle, indicating possible REM sleep rebound. After 4 weeks of abstinence, REM sleep time remained reduced in females but was recovered in males. Although REM sleep quantity was decreased, there was no change in REM sleep quality, measured with total number of bouts and average bout duration. In non-REM (NREM) sleep in males, however, while total quantity of NREM sleep was unchanged, average NREM bout duration decreased and number of bouts increased in the dark cycle during withdrawal, indicating NREM sleep quality was more fragmented during the dark cycle. LEM had no significant effect on NREM sleep in males or females. Male rats also showed no change in total amount of wakefulness (WAKE) during abstinence but did show an increase in the number of WAKE bouts and a decrease in WAKE average bout duration during the light and dark cycles. After 4 weeks of abstinence, NREM and WAKE fragmentation remained unresolved. Overall, these findings show that REM and NREM sleep are dysregulated during abstinence from MAV and that HCRT neurotransmission likely contributes to the disrupted sleep. These findings also show possible sex differences in response to MA vapor administration.

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Apr 5th, 9:00 AM Apr 5th, 11:30 AM

Insomnia treatment drug lemborexant rescues REM sleep dysfunction associated with methamphetamine vapor withdrawal

D.P. Culp Center Ballroom

Insomnia treatment drug lemborexant rescues REM sleep dysfunction associated with methamphetamine vapor withdrawal Huffcutt, Galen P., Jones, Marissa R. and Schmeichel, Brooke E.  Biomedical Sciences Department, Quillen College of Medicine, East Tennessee State University, Johnson City, TN USA In 2021, 2.5 million people abused the psychostimulant drug methamphetamine (MA) in the U.S. Chronic MA use can lead to disordered sleep, particularly during withdrawal, and clinical studies show that sleep dysfunction is a strong predictor for relapse. The neuropeptide hypocretin (HCRT) plays a critical role in the transition from sleep to wakefulness and also modulates drug reward. Enhanced HCRT signaling in the brain underlies the sleep disorder insomnia and the dual-HCRT-receptor antagonist lemborexant (LEM) is prescribed for treatment of insomnia in humans. Here we characterized sleep dysfunction associated with MA vapor (MAV) withdrawal in rats and hypothesized that HCRT signaling contributes to poor sleep. Adult Wistar rats (N=15, 8M/7F) received a telemetry device implant and EEG/EMG signals were recorded for 23 hours (12h light:11 h dark). Rats were exposed to passive MAV for 4 weeks to induce dependence. Rats showed significant increases in maximum body temperature and decreases in novel object recognition during drug withdrawal. Sleep/wake data were analyzed prior to MAV exposure (baseline; BL), during withdrawal (1 week of MAV abstinence), and during protracted abstinence (four weeks of MAV abstinence). LEM (0 and 30 mg/kg, counter-balanced) was administered at the beginning of the light cycle immediately prior to 1-week, and 4-week sleep recordings. After 1 week of abstinence, rats showed a decrease in rapid eye movement (REM) sleep time in the light cycle during withdrawal, while LEM restored this REM sleep. There was also an increase in REM sleep time in males during the dark cycle, indicating possible REM sleep rebound. After 4 weeks of abstinence, REM sleep time remained reduced in females but was recovered in males. Although REM sleep quantity was decreased, there was no change in REM sleep quality, measured with total number of bouts and average bout duration. In non-REM (NREM) sleep in males, however, while total quantity of NREM sleep was unchanged, average NREM bout duration decreased and number of bouts increased in the dark cycle during withdrawal, indicating NREM sleep quality was more fragmented during the dark cycle. LEM had no significant effect on NREM sleep in males or females. Male rats also showed no change in total amount of wakefulness (WAKE) during abstinence but did show an increase in the number of WAKE bouts and a decrease in WAKE average bout duration during the light and dark cycles. After 4 weeks of abstinence, NREM and WAKE fragmentation remained unresolved. Overall, these findings show that REM and NREM sleep are dysregulated during abstinence from MAV and that HCRT neurotransmission likely contributes to the disrupted sleep. These findings also show possible sex differences in response to MA vapor administration.