# Sex Difference in a rodent model of co-occurrence of chronic stress and cocaine use disorder

> **NIH NIH U54** · PONCE SCHOOL OF MEDICINE · 2024 · $459,605

## Abstract

Summary:
Despite the high rate of co-occurrence between substance use disorders (SUDs) and other mental illness the
neurophysiological mechanisms that underlie the stress/drug abuse comorbidity are not well understood. In
addition, some mental illnesses, such as anxiety, depression, trauma and stressor-related disorders, are
identified as risk factors for developing drug addiction. Studies have also shown gender-related health disparities
and health care disparities, with women having higher rates of comorbidity between SUDs and other mental
illnesses than men, but lower rates of treatment. Taken together, these studies highlight the need to recognize
how traumatic experiences affect neural responses to drug use in males and females. Research in our laboratory
combines validated rat models of severe stress and drug self-administration, which allow us to disentangle the
relationships between a history of stress and behavioral responses to cocaine. Preliminary results show that
inescapable footshocks (IFS) – a form of chronic stress - prior to cocaine self-administration (SA), decrease
cocaine consumption in female rats, but not in males. On the other hand, stressed-female rats show an increase
in cue reactivity after 30 days of forced abstinence, which is not observed in male rats. These results suggest
that chronic stress prior to cocaine exposure enhances the rewarding effects of cocaine during drug acquisition,
leading to increased craving incubation. Based on the need to understand the relationship between stress and
drug use, as well as these preliminary data, the goal of this study is to understand how a history of prior chronic
stress can influence behavioral and neurophysiological responses to cocaine in both males and females. Two
brain structures that contribute to the development of both severe stress and cocaine use disorders (CUD) are
the basolateral amygdala (BLA) and the nucleus accumbens (NAc). However, the effects of chronic stress and
cocaine exposure on synaptic plasticity of BLA neurons projecting to the NAc in males are still unclear and, in
females, completely unknown. Accordingly, we propose to specifically assess how IFS prior to extended access
cocaine self-administration differentially affects the neurophysiology of BLA neurons projecting to the NAc core
of females versus males, in connection with cocaine-related behaviors. We will utilize a chronic stress and CUD
comorbidity rodent model and whole cell patch-clamp recordings to measure synaptic plasticity in the NAc core
after self-administration (Aim 1), and BLA to NAc core synaptic changes after forced abstinence (Aim 2).
Additionally, a designer receptor exclusively activated by manipulations with designer drugs (DREADDs) will be
used to assess functional contributions of the BLA-NAc core circuitry during self-administration and cue reactivity
(Aim 3). Understanding how stress affects neural plasticity in a way that leads to increased cocaine-seeking
behavior in femal...

## Key facts

- **NIH application ID:** 10797610
- **Project number:** 2U54MD007579-39
- **Recipient organization:** PONCE SCHOOL OF MEDICINE
- **Principal Investigator:** Marian Talimar Sepulveda-Orengo
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $459,605
- **Award type:** 2
- **Project period:** 1997-08-25 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797610

## Citation

> US National Institutes of Health, RePORTER application 10797610, Sex Difference in a rodent model of co-occurrence of chronic stress and cocaine use disorder (2U54MD007579-39). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10797610. Licensed CC0.

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