NIH R01: Mechanistic Studies to Investigate the Interrelationship Between Sleep and/or Circadian Rhythms and Substance Use Disorders

Funding Opportunity Number: RFA-DA-25-045

Letter of Intent: September 29, 2024
Submission: October 29, 2024


Substance use disorders (SUDs) and disorders of sleep/circadian rhythms are intricately interconnected. Sleep dysregulation including insufficient sleep duration, altered sleep architecture, poor sleep quality and irregular circadian rhythm is prevalent in >75% of individuals with SUDs and represents a challenge to recovery. Conversely, acute and chronic exposure to addictive substances influences sleep and circadian rhythms. The substantial overlap between neuronal systems and processes involved in SUD and sleep/circadian rhythm likely underlies these interactions. However, this has not been systematically investigated at a mechanistic level and the regulation of sleep/circadian rhythms has not been fully integrated with the neurobiology of SUD mechanisms and risk factors. Mechanistic studies that determine the directionality of sleep and SUD interactions are needed to understand fundamental processes linking SUD and sleep/circadian dysregulation, and further, to identify new targets for prevention and improved therapy.

There are several brain regions and neurotransmitter substrates that regulate arousal, sleep/circadian rhythms, as well as motivation and reward. Diverse systems including locus coeruleus noradrenergic neurons, serotonergic neurons in the raphe, basal forebrain cholinergic neurons, midbrain dopaminergic neurons, hypothalamic hypocretin (orexin) – ergic neurons, the endocannabinoid and histaminergic systems and their projections regulate arousal and sleep while also having known roles in reward-related behaviors. However, little is known about how these brain regions, neural circuits, neurotransmitter, and receptor systems mechanistically intersect to cause a bidirectional interaction between sleep/circadian rhythms and SUDs.

The goal of this Notice of Funding Opportunity (NOFO) is to support basic and pre-clinical research project applications that explore the mechanisms that underlie the interrelationship between sleep and/or circadian rhythms and SUDs. Applicants may propose research projects using behavioral, cognitive, cellular, circuit, genetic, molecular, imaging, pharmacological, and/or computational approaches.

Research Objectives

The National Institute on Drug Abuse (NIDA) seeks to stimulate research targeted at understanding the mechanisms that underlie the intersection of sleep and/or circadian rhythms and SUDs. These studies will investigate how sleep, alterations in sleep homeostasis, alterations in circadian rhythms and/or sleeping disorders influence substance use, substance dependence, withdrawal, relapse and/or recovery from SUDs. Interdisciplinary teams with the ability to integrate research expertise in sleep/circadian rhythms with the neurobiology of SUDs are encouraged.

Research questions of programmatic interest include, but are not limited to:

  • How does sleep/circadian rhythm mechanistically influence substance use, substance dependence, reward, withdrawal and/or relapse? Does restoring sleep duration and/or architecture influence the trajectory of SUDs? What are the underlying mechanisms?
  • What are the neurobiological mechanisms by which addictive substances alter sleep/circadian rhythms?
  • How does alteration in sleep/circadian rhythms induced by addictive substances mechanistically influence the addiction trajectory?
  • What brain regions, signaling molecules, neurotransmitter systems, brain circuits, genetic and epigenetic mechanisms underlie the effect of sleep/circadian disturbances in the development, progression or exacerbation of SUDs?
  • What are the mechanisms by which neurocognitive constructs relevant to SUDs such as learning, memory, emotional regulation, social cognition, and decision-making are impacted by sleep/circadian disruption?
  • What are the mechanisms underlying the effect of sleep/circadian disruptions on large-scale brain network dynamics?
  • Are there sex and gender differences in the impact of sleep/circadian disruption on SUDs or in the effect of acute or chronic exposure to drugs on sleep physiology or circadian rhythms? What are the underlying mechanisms?
  • What is the impact of sleep/circadian disturbances during adolescence on the risk for the development of SUDs? What is the underlying neurobiology? How does this differ from the impact on adults?

For more information, please see the opportunity webpage.