# Investigating the long-term effects of prenatal circadian rhythm disruption on substance use-related disorders

> **NIH NIH K99** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $134,662

## Abstract

Project Summary/Abstract
Circadian rhythms are a vulnerability factor associated with substance use. Drugs of abuse entrain and disrupt
circadian rhythms and those with disrupted rhythms are vulnerable to developing substance use disorders,
creating a vicious cycle. At least 20% of Americans are at risk for environmental circadian rhythm disruptions
(CRD) due to working nonstandard shifts, including evening, night or rotating shift work. Shift workers are at risk
for substantial negative health outcomes, but females are particularly affected due to greater vulnerability for
substance use and additional negative outcomes associated with pregnancy. Not only do female shift workers
experience adverse outcomes during pregnancy, but offspring are also affected, both at birth and later in life.
Specifically, depression, risky behavior and substance use are all increased in the offspring of shift workers.
Importantly, prenatal CRD (pCRD) in mice recapitulates these risks, increasing adverse pregnancy outcomes
and anxiety-like behavior in adult offspring. These consistent results across species suggest environmental CRD
via light/dark cycle shifting in rodents is a good translational model for studying the outcomes of prenatal
disruptions in humans. Although substance use is associated with shift work, in parents and offspring, it is unclear
how pCRD induces long-term risk for substance use. In my preliminary experiments, I measured a variety of
substance use-related outcomes in adult mice with pCRD. I found consistent sex differences where male
offspring of dams with CRD showed a profound substance use-like phenotype, with increased drug preference,
food self-administration, reinforcing and motivational properties of cocaine. On the other hand, female offspring
showed an opposite, anhedonic-like phenotype with decreased food self-administration, cocaine self-
administration and the reinforcing properties of cocaine, as well as maladaptive premature habit formation. Since
drugs of abuse entrain circadian rhythms, increasing craving and seeking when drugs are anticipated, increased
reward sensitivity in males after pCRD could be due to underlying changes in circadian rhythms. In addition,
evidence from our lab suggests that altered circadian rhythms in reward-related brain regions, through genetic
manipulations, directly effect behavioral responses to cocaine. These data suggest that pCRD disrupts circadian
rhythms in locomotor activity and reward in adulthood, perhaps by altering the expression and rhythmicity of
circadian and circadian-regulated genes. Developmental hormones are also a potential factor that could impact
sex-specific effects of pCRD since exposure to gonadal hormones during sensitive periods induces long-term
changes to the brain and behavior (organizational). Therefore, the hypothesis of this proposal is that pCRD
interacts with developmental, organizational hormones to alter rhythms in reward, locomotor activity rhythms and
gene expres...

## Key facts

- **NIH application ID:** 10349186
- **Project number:** 1K99DA055064-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Lauren Marie DePoy
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $134,662
- **Award type:** 1
- **Project period:** 2022-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10349186

## Citation

> US National Institutes of Health, RePORTER application 10349186, Investigating the long-term effects of prenatal circadian rhythm disruption on substance use-related disorders (1K99DA055064-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10349186. Licensed CC0.

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