# Sleep regulates drug relapse and addiction

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $352,125

## Abstract

Abstract
Sleep abnormalities commonly occur among chronic cocaine users after withdrawal, including loss of total
sleep time and increase in sleep fragmentation. The withdrawal-associated sleep problems are speculated to
foster cocaine use and relapse, however, whether and how sleep mechanisms may regulate the brain reward
circuitry and impact relapse-like behaviors remain elusive. Using a rat cocaine self-administration model to
recapitulate sleep loss and fragmentation after withdrawal, the Huang lab has obtained direct evidence of
sleep-induced regulation of cocaine seeking: experimentally increasing REM (without changing NREM) sleep
episode durations reduces cocaine seeking after withdrawal, suggesting REM sleep-associated mechanisms in
this regulation. Neural mechanism studies have focused on the nucleus accumbens (NAc), a key brain region
for reward processing. Progressive accumulation of the GluA1-rich, calcium-permeable, AMPA receptors (CP-
AMPARs) at synapses in the NAc critically contributes to the intensified cocaine seeking after withdrawal.
Importantly, behavioral sleep interventions that increase REM sleep episode durations lead to decreased
accumulation of NAc synaptic CP-AMPARs. These results not only suggest NAc CP-AMPARs as key neuronal
substrates that express REM sleep-induced anti-relapse effects, but raise the critical question – how do REM
sleep interventions route to NAc CP-AMPARs? Published and preliminary results suggest that the melanin-
concentrating hormone (MCH) neurons in the lateral hypothalamus and zona incerta (LH for short) may play an
important role in the REM sleep-induced anti-relapse effects. LH MCH neurons predominantly fire during REM
sleep. Behaviorally induced sleep rebound after REM sleep restriction, a strategy utilized by our sleep
intervention, further enhances the activity of these neurons. Moreover, MCH neurons project to the NAc, where
MCH receptors (MCHRs) are highly expressed; MCHR signaling in the NAc strongly regulates the
phosphorylation and facilitates synaptic removal of GluA1-containing AMPARs. Preliminary results further
show that LH MCH neurons exhibited reduced membrane excitability after withdrawal from cocaine, whereas
mimicking MCH release by intra-NAc infusion of MCH during light (sleep) phase led to reduction of synaptic
CP-AMPARs in the NAc and decreased withdrawal-associated cocaine seeking. Together, these results
suggest that REM sleep interventions may engage LH MCH neural activity to produce anti-relapse effects after
withdrawal. This application will test the hypothesis that MCH signaling during sleep contributes to REM
sleep-induced anti-relapse effects after withdrawal from cocaine. In contrast to the current practice
focusing on NREM sleep, this proposal will identify a novel REM sleep mechanism that produces anti-relapse
effects. Moreover, the proposal emphasizes target manipulations during sleep rather than in wakefulness.
Concerning the high comorbidity between drug wit...

## Key facts

- **NIH application ID:** 10350587
- **Project number:** 5R01DA046491-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Yanhua H Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $352,125
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10350587

## Citation

> US National Institutes of Health, RePORTER application 10350587, Sleep regulates drug relapse and addiction (5R01DA046491-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10350587. Licensed CC0.

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