# Molecular Studies of Cocaine Action in Brain

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $595,378

## Abstract

SUMMARY
This R01 grant has focused on long-lasting changes induced by stimulant and opioid drugs of abuse in the
brain's reward circuitry in rodent models. Our aims have shifted over the years based on an expanding knowl-
edge of addiction mechanisms and development of more powerful experimental methods. When the grant was
last renewed competitively, it focused on transcription factors that mediate drug regulation of gene expression.
Recently, we have shifted increasingly to a host of chromatin-based mechanisms—so-called epigenetics—that
work in concert with transcription factors to alter expression levels of target genes. Our central hypothesis is
that drug exposure induces stable “chromatin scars” that drive particularly long-lived changes in gene
expression, which in turn mediate many downstream changes in cell and circuit function and behavior. Here,
we concentrate on the nucleus accumbens (NAc) based on its central role in brain reward and our empirical
finding that it is most dramatically affected by drugs of abuse in our RNA-seq datasets across numerous brain
reward regions. In Aim 1, we utilize cocaine or heroin self-administration in mice, combined with unbiased
RNA-seq, ATAC-seq, and proteomic methods, to identify candidate chromatin-scar mechanisms in each of the
two major subtypes of NAc medium spiny projection neurons, D1- and D2-type MSNs. We then use ChIP-seq
to map those candidate mechanisms genome-wide in the affected cell type. In Aim 2, we use viral-mediated
gene transfer to bidirectionally manipulate the most highly implicated chromatin-scar mechanisms in a cell-
type-specific manner to causally establish their role in mediating the lasting transcriptional and behavioral
consequences of drug self-administration. We have already identified two prominent chromatin scars. After
prolonged (30 days) withdrawal from cocaine or heroin self-administration, there is profound depletion of
H2A.Z (a variant of the core histone subunit H2A) and its acetylated form (H2A.Zac) in both D1 and D2 MSNs,
and such depletion associates extensively with those RNAs that show primed or desensitized expression at
this time point, an effect particularly prominent in D1 MSNs. Moreover, several of the proteins that control
H2A.Z deposition or eviction from nucleosomes or its acetylation are prominently regulated selectively in D1
NAc MSNs. We also have evidence for a role played by H3K79me2 (dimethylation of histone 3 Lys 79) which
is induced in NAc after prolonged withdrawal. The histone methyltransferase (DOT1L) and demethylase
(KDM2B) that catalyze and remove this mark, respectively, are regulated in D1 and in D2 MSNs. We will now
manipulate each of these proteins in a cell-type-selective manner and study downstream behavioral and
transcriptional effects. We already have shown that DOT1L knockdown in D1 NAc MSNs profoundly reduces
rewarding responses to cocaine. It is important to note that neither H2A.Z nor H3K79me2 have been studied
previously in add...

## Key facts

- **NIH application ID:** 10205671
- **Project number:** 2R01DA007359-33
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** ERIC J. NESTLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $595,378
- **Award type:** 2
- **Project period:** 1991-08-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205671

## Citation

> US National Institutes of Health, RePORTER application 10205671, Molecular Studies of Cocaine Action in Brain (2R01DA007359-33). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10205671. Licensed CC0.

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