# Cell Specificity of the Human Heroin Epigenome

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $538,249

## Abstract

Project Summary
 Opiate abuse and overdose have risen to epidemic proportions in the USA in recent years. Only limited
medication options are currently available, which is in large part due to the surprising lack of knowledge about
the pathophysiologic mechanisms that underlie opiate addiction. Recent animal studies have provided robust
evidence that repeated drug exposure induces changes in gene expression through alterations in epigenetic
regulation that are linked to addiction-related behavioral abnormalities. However, information about the
epigenetic landscape in the brains of human addicts remains limited and is critical for the development of
clinically effective treatments.
 Recent studies have achieved a comprehensive mapping of brain-specific epigenetic marks in the
human genome using homogenate postmortem tissue. However, cellular heterogeneity of the brain precludes
a reliable annotation of cell-type-specific epigenetic modifications from these data. Aim1 of this project will
leverage our newly developed molecular strategies to illuminate the neural subtype-specific epigenome of
heroin addiction with unprecedented detail—in four different populations of brain cells—which will highly
enhance the likelihood of identifying cell-type-specific signatures of addiction-associated epigenetic variations.
 Our recent epigenetic studies in glutamatergic (Glu) projection neurons and inhibitory GABA
interneurons from the human orbital frontal cortex (OFC) suggest that many activity-dependent genes (ADGs)
are “poised” to be activated in a neuron-subtype-specific manner. ADGs are activated by experience-driven
synaptic activity (including exposure to addictive drugs) and regulate diverse aspects of the nervous system,
(including synaptic plasticity). Notably, our recent RNA-seq data in homogenate OFC samples showed that
among the most significant changes is the downregulation of a subset of the ADGs. These results are in line
with the growing body of literature that implicates diminished output from the ventral aspects of the prefrontal
cortex in drug addiction. We hypothesize that the steady-state expression and inducibility of the ADGs (the
latter is determined by their epigenetic milieu) are altered in heroin addicts in a neuron-subtype-specific
manner, and we will test this hypothesis in Aim 2. Considering the importance of ADGs in synaptic plasticity
that accompanies the development and maintenance of drug addiction, in Aim 2 we will utilize a translational
animal model to explore the cell-specific functional contribution of ADGs to heroin self-administration behavior.
 Overall, this innovative line of research will develop unique datasets that will be available to the
research community and will provide an urgently needed resource for genome-wide neural subtype-specific
chromatin and transcriptome maps in heroin abuse and normal subjects. Moreover, the mechanistic studies in
animal models can promote the development of novel therapeutic interve...

## Key facts

- **NIH application ID:** 10159879
- **Project number:** 5R01DA043247-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** STELLA DRACHEVA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $538,249
- **Award type:** 5
- **Project period:** 2017-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159879

## Citation

> US National Institutes of Health, RePORTER application 10159879, Cell Specificity of the Human Heroin Epigenome (5R01DA043247-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10159879. Licensed CC0.

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