# Sex differences in stress inoculation of addiction-like phenotypes

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2022 · $115,577

## 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:** 10609158
- **Project number:** 3R01DA049837-03S1
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Debra A Bangasser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $115,577
- **Award type:** 3
- **Project period:** 2020-07-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10609158

## Citation

> US National Institutes of Health, RePORTER application 10609158, Sex differences in stress inoculation of addiction-like phenotypes (3R01DA049837-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10609158. Licensed CC0.

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