# Orexin (hypocretin) signaling in ventral tegmental area as a common mediator of sleep disturbances and drug demand in cocaine abstinence

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $372,867

## Abstract

Summary/Abstract: Initial cocaine abstinence is associated with severe sleep disturbances. Poor sleep is one
of the strongest predictors of return to use (relapse), suggesting potential overlap in brain arousal and reward
networks. Separate literatures link orexin (hypocretin) neurons in lateral hypothalamus (LH) to the regulation of
wake and drug motivation, yet how these neurons might commonly contribute to sleep disturbances and
subsequent drug use in CUD is not well understood. In rats, the intermittent access (IntA) schedule of cocaine
self-administration increases cocaine demand, a behavioral economics measure of drug motivation. These
motivational changes are persistent and are further enhanced following protracted abstinence. We showed that
cocaine IntA is associated with an increase in the number and activity of orexin producing neurons, and that
these increases are causally linked to cocaine demand. Our preliminary studies indicate that cocaine IntA rats
also exhibit sleep dysregulation during initial abstinence, characterized by excessive wakefulness and a
corresponding reduction in NREM (non-rapid eye movement) sleep. In Aim 1, we test if these sleep disturbances
persist throughout protracted (28d) abstinence following cocaine IntA, and how they are related to population
activity of orexin neurons throughout the inactive period. Using a chemogenetic approach, we predict that
normalizing orexin neuronal activity during the inactive period will improve sleep outcomes and reduce cocaine
demand following protracted abstinence. In Aim 2, we test if orexin projections to ventral tegmental area (VTA)
are involved in mediating excessive wakefulness during cocaine abstinence. This is based on our preliminary
data showing that waking is associated with increased orexin binding in VTA, as determined by the novel
OxLight1 sensor. We predict OxLight1 signal in VTA will be enhanced in IntA rats during early and protracted
abstinence, and that chemogenetic inhibition of VTA-projecting orexin neurons will normalize both sleep and
cocaine demand outcomes at both timepoints. We will also determine how IntA changes levels of orexin 1 (Ox1R)
vs orexin 2 (Ox2R) receptors in VTA and their functional role in mediating arousal and cocaine demand during
abstinence. Finally, in Aim 3, we test the potential utility of repurposing the FDA approved dual Ox1R/Ox2R
antagonist suvorexant for use in CUD. We predict that daily dosing with suvorexant, administered immediately
prior to the inactive period, will normalize sleep and reduce drug motivation in IntA rats. Based on data indicating
that suvorexant can persistently reduce orexin levels, we also predict that chronic suvorexant will normalize
orexin cell numbers and their input to VTA, and thus reduce drug demand beyond the treatment period. Together,
these studies combine several cutting-edge approaches to determine how orexin neurons, and their inputs to
VTA, might serve as a neurobiological link between sleep ...

## Key facts

- **NIH application ID:** 10985792
- **Project number:** 1R01DA061303-01
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Gary S. Aston-Jones
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $372,867
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985792

## Citation

> US National Institutes of Health, RePORTER application 10985792, Orexin (hypocretin) signaling in ventral tegmental area as a common mediator of sleep disturbances and drug demand in cocaine abstinence (1R01DA061303-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10985792. Licensed CC0.

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