# Diurnal rhythms in the nucleus accumbens: Mechanisms and role in substance use disorders

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $414,329

## Abstract

Abstract
Substance use disorders (SUD) are a major public health problem that impact millions of people and their
families. The factors that contribute to SUD vulnerability, as well as the transition from drug use to abuse to
SUD remain unclear. We know that the reward value for alcohol and drugs of abuse normally varies by time of
day. For example, for most individuals, the desire to drink wine or beer is very different at 6:00am compared to
6:00pm. There is a normal, time of day dependent, rhythm in the reward value for these drinks and this rhythm
is protective against SUD. In fact one of the key factors that is used to evaluate the transition to addiction is the
loss of diurnal rhythmicity in reward value (the desire to drink alcohol in the morning for example). In addition to
alcohol, when the reward circuitry has been hijacked by chronic exposure to other drugs of abuse, circadian
rhythms in reward circuitry are lost, and these rewards overtime develop equal value at any time of day.
Genetic factors (circadian gene variations) also contribute to reduced rhythms in reward at baseline, prior to
any drug exposure, and increased SUD-related vulnerability. Indeed mice with circadian gene mutations show
greater drug self-administration and a loss in the normal diurnal rhythm in this behavior. By determining the
molecular and cellular mechanisms that underlie natural diurnal rhythms in reward, we can potentially help
prevent the transition between use to abuse to SUD. Our previous studies have found strong diurnal
differences in many aspects of reward circuitry including excitability of neurons in the nucleus accumbens
(NAc). We have also found that the circadian protein, NPAS2 plays an important role in the NAc in the
regulation of drug reward. In this R01 renewal, we first want to determine if this diurnal difference in excitability
is similar in D1R, D2R or cholinergic cells, if it is similar in males and females, if Npas2 mutants have disrupted
rhythmicity in MSN excitability, and if this rhythmicity is altered by chronic cocaine self-administration. We then
want to identify at a transcriptome level what actively transcribed genes have diurnal rhythms in specific cell
types in the NAc. This will help us identify the molecular mechanisms underlying these normal diurnal
differences in evoked response. We will then determine how these molecular rhythms are altered with chronic
cocaine self-administration. Finally, we will test particular molecular factors to determine their role in regulating
diurnal rhythms in excitability. Taken together, the study of the mechanisms that underlie diurnal rhythmicity in
reward are important and can help us develop future treatments that help maintain and strengthen these
normal rhythms.

## Key facts

- **NIH application ID:** 10065160
- **Project number:** 2R01DA039865-06A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Colleen A McClung
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $414,329
- **Award type:** 2
- **Project period:** 2015-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065160

## Citation

> US National Institutes of Health, RePORTER application 10065160, Diurnal rhythms in the nucleus accumbens: Mechanisms and role in substance use disorders (2R01DA039865-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10065160. Licensed CC0.

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