# Unraveling epigenetic mechanisms of opioid addiction susceptibility using multigenerational animal models

> **NIH NIH DP1** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $475,500

## Abstract

Drug addiction is a massive public health concern that inflicts extensive burdens on our
economy and society. The harmful consequences of drug abuse extend far beyond the addicts
and gravely impact their families. A growing body of evidence suggests that the children of
fathers who consumed drugs around the time of conception show altered brain function and
behavioral abnormalities. We have established a highly translational paradigm of paternal opioid
drug taking, using morphine self-administration in rats to study this phenomenon. Our results
demonstrate that the male progeny of fathers (sires) that took morphine chronically are more
susceptible to develop addiction-like traits and self-administer morphine. This multigenerational
animal model offers a rare window into a pool of subjects that are more vulnerable to develop
addiction, a population that has been historically difficult to identify. Here, we can reliably and
systematically produce animals that show increased drug taking behavior, which offers a unique
opportunity to delve into the mechanisms underlying addiction susceptibility. This multifaceted
project will combine behavioral and molecular biological approaches to identify functionally
relevant mechanisms that confer a higher propensity to develop addiction.
The proposed studies will address two major questions: (1) which germline epigenetic
reprogramming events are critical for shaping development toward addiction vulnerability into
adulthood? (2) what are the functionally relevant neuro-epigenetic processes that increase
addiction-like behavior in our multigenerational model of drug taking? This proposal will
delineate biomarkers of addiction by identifying changes in sperm miRNA expression and DNA
methylation caused by chronic paternal morphine exposure. We hypothesize that the opioid-
derived sperm molecular signature is predictive of addiction susceptibility in the resulting
progeny. We will directly test this possibility by assessing the functional relevance of specific
sperm methyl marks and individual sperm miRNAs in shaping neurodevelopment toward higher
drug taking and elevated drug reinforcing efficacy in adult animals. We will also probe covalent
modifications of nuclear histone proteins that package DNA in the brains of adult morphine-sired
progeny that show increased drug taking. Gene-targeted epigenetic editing will be used to
characterize histone marks that regulate drug taking behavior in neural reward circuits. This
research will establish a strategy to delineate functional mechanisms associated with addiction
susceptibility and develop a platform to study how environmental insults can shape and affect
the likelihood of individuals to develop psychiatric diseases.

## Key facts

- **NIH application ID:** 10159231
- **Project number:** 5DP1DA046537-04
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Mathieu Wimmer
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $475,500
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159231

## Citation

> US National Institutes of Health, RePORTER application 10159231, Unraveling epigenetic mechanisms of opioid addiction susceptibility using multigenerational animal models (5DP1DA046537-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10159231. Licensed CC0.

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