# Role of prelimbic cortical endocannabinoid signaling in enhanced cocaine-seeking behavior following combined repeated stress and cocaine use in rats

> **NIH NIH R37** · UNIVERSITY OF CINCINNATI · 2024 · $440,054

## Abstract

Project summary/Abstract
Addiction remains a vast problem in the United States and complicating the issue is the lack of FDA-approved
medications for the treatment of cocaine use disorder (CUD) making it a critical unmet need. A difficulty in
identifying treatment options is that CUD is multi-faceted involving interactions among several external factors,
including stress, which is unavoidable in daily life. Despite the prevalence of stress in human populations of
CUD, most pre-clinical addiction research does not incorporate stress as a factor during periods of drug use.
To examine the importance of stress-cocaine interactions on cocaine use and seeking behavior we use a
model where, in rats demonstrating otherwise stable cocaine self-administration (SA), a stressor delivered
daily at the time of cocaine SA, escalates cocaine intake and enhances cocaine-seeking behavior. This likely
involves neurobiological mediators that connect stress-responsive and reward systems in the brain, such as
endocannabinoid signaling (eCB). In support of this, systemic administration of a cannabinoid receptor 1
antagonist attenuates cocaine-induced reinstatement only in rats with a history of stress. Furthermore, we have
localized this effect to the prelimbic cortex (PrL), a key site for regulation of stress and drug-seeking behavior.
Importantly, eCB signaling, through attenuation of inhibitory neurotransmission, is well positioned to regulate
PrL pyramidal neuron activity and output which ultimately results in expression of enhanced cocaine-seeking
behavior. This proposal tests the novel hypothesis that repeated stress at the time of cocaine SA produces
long-lasting upregulation of eCB signaling in the PrL leading to increased pyramidal neuron activity and drug-
seeking behavior through dysregulated GABAergic signaling. To test this hypothesis, we will use behavioral,
molecular, and neurophysiological techniques to assess the involvement of PrL eCB signaling in the long-term
consequences of repeated stress-cocaine interactions. First, we will assess the role of PrL eCB signaling, via
pharmacological manipulation, in enhanced cocaine-induced reinstatement in stress-escalated rats. We will
then identify how combined repeated stress and cocaine SA regulates PrL eCB signaling by quantifying cell
type-specific changes in molecular components of the eCB system using fluorescent in situ hybridization, and
measure changes in PrL eCB content with mass spectrometry following cocaine-induced reinstatement. Lastly,
we will examine changes in eCB-mediated inhibitory synaptic plasticity that are associated with enhanced
cocaine-induced reinstatement, using whole-cell patch clamp recordings in the PrL. We will also use in vivo
fiber photometry measurement of Ca2+signaling to identify the contribution of eCB signaling to changes in PrL
pyramidal neuron activity associated with enhanced cocaine-induced reinstatement. These studies will provide
much needed information about how stre...

## Key facts

- **NIH application ID:** 10801155
- **Project number:** 1R37DA057944-01A1
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Jayme Rose McReynolds
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $440,054
- **Award type:** 1
- **Project period:** 2024-03-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801155

## Citation

> US National Institutes of Health, RePORTER application 10801155, Role of prelimbic cortical endocannabinoid signaling in enhanced cocaine-seeking behavior following combined repeated stress and cocaine use in rats (1R37DA057944-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10801155. Licensed CC0.

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