# Sex differences in stress inoculation of addiction-like phenotypes

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $13,948

## Abstract

Opioid use disorder is on the rise and the economic and human cost is staggering. It remains unclear why only
a subset of people who take opioids develop dependence, prompting efforts to understand factors that promote
vulnerability to opioid misuse. However, it is also critical to identify factors that promote resilience to substance
use disorder (SUD). Experiences early in life can alter risk/resilience for the later development of disorders. For
example, early life stress that is not overwhelming can have an “inoculating” effect that promotes the
development of resilience in adulthood. Here we use a rat model of early life adversity, the limited bedding and
nesting (LBN) model, to assess how this manipulation affects addiction-like phenotypes in adulthood. In LBN,
dams and their pups are exposed to a low resource environment during the pups first week of life, which
induces stress in the pups. We found that LBN inoculates males against addiction-like behaviors, such that
adult male rats exposed to LBN self-administer less morphine and are less motivated to take morphine than
adult males raised in a normal, adequately resourced, nesting environment. Impulsive choice, a risk factor for
SUD, was also assessed, and LBN reduced impulsive choice in males. LBN had no effect on these behaviors
in female rats. This proposal will determine how LBN further alters addition-like behaviors, as well as changes
the physiology and the transcriptome of the nucleus accumbens (NAc), a region that critically mediates drug
intake and impulsivity. Aim 1 will test the hypothesis that LBN shifts the dose-response curve for morphine
self-administration to the right in males. This aim will also determine if LBN reduces both impulsive choice and
impulsive action in males. Consistent with our preliminary data, behavioral changes following LBN in females
are not expected. Aim 2 will test the hypothesis that LBN reduces glutamatergic transmission in the NAc of
males, but not females, an effect that would promote resilience to the reinforcing efficacy of morphine. Prior
work has demonstrated that early life experience can reprogram the brain through epigenetic modifications that
lead to persistent changes in gene expression and neuronal signaling. Thus, Aim 3 will identify sex-specific
changes in gene expression and accompanying chromatin remodeling events in the NAc elicited by LBN. Our
preliminary data reveal that LBN reduces the expression of several glutamate signaling genes in males.
Certain histone deacetylases (HDACs), enzymes that remove acetyl groups from histone tails, are implicated
in these gene changes. We will test the behavioral relevance of these HDACs by manipulating their function
within the NAc and determining whether they mediate resilience to addiction-related behavior. Collectively, this
proposal will reveal mechanisms by which LBN can inoculate males against addiction-like phenotypes.
Notably, our team of investigators is uniquely positioned to assess ...

## Key facts

- **NIH application ID:** 10399329
- **Project number:** 3R01DA049837-02S2
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Debra A Bangasser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $13,948
- **Award type:** 3
- **Project period:** 2020-07-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399329

## Citation

> US National Institutes of Health, RePORTER application 10399329, Sex differences in stress inoculation of addiction-like phenotypes (3R01DA049837-02S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10399329. Licensed CC0.

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