# Roles for histone monoaminylation in cocaine-induced transcriptional and behavioral plasticity

> **NIH NIH DP1** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $508,500

## Abstract

Project Summary: Maze, IS, Ph.D.
Persistent changes in neuronal gene expression promote physiological alterations implicated in a wide variety
of human neurodevelopmental and adult psychiatric disorders. More recently, cell-type and brain region
specific `epigenetic' mechanisms have been demonstrated to regulate transcriptional programs contributing to
addiction-like behaviors; however, our understanding of how these mechanisms mediate life-long addiction
remains limited. Monoaminergic neurotransmission in the central nervous system plays a critical role in
psychostimulant-induced neural plasticity, with alterations in monoamine production/function being implicated
in both the development and treatment of substance abuse disorders. Although packaging of monoamines by
the vesicular monoamine transporter is essential for numerous aspects of reward, recent data have
demonstrated the additional presence of `reserve' pools of extravesicular monoamines in the nucleus of
monoamine producing neurons. Dopamine, as well as other monoamines, has previously been shown to form
covalent bonds with certain cytoplasmic proteins catalyzed by the tissue Transglutaminase 2 enzyme. We
recently identified histone proteins – histones are highly abundant, post-translationally modified proteins, which
constitute the building blocks of eukaryotic chromatin and form the fundamental repeating units of transcription
in mammalian cells – as robust substrates for monoaminylation in brain. Our data indicate that histone H3
dopaminylation likely acts to potentiate binding of adjacent histone posttranslational modification (PTM)
interacting proteins (`readers') and may play a direct and critical role in dopaminergic neuronal transcription.
Furthermore, our data demonstrate that chronic withdrawal from volitional administration of extended access to
cocaine in rodents results in high levels of dopamine accumulation in the nucleus of dopamine producing
neurons in the ventral tegmental area (an important structure within the mesolimbic reward circuitry), as well as
increased cytoplasmic to nuclear shuttling of TGM2, the H3 dopaminylase. Take together, these data suggest
that persistent states of addiction may result from increased genomic enrichment of H3 dopaminylation,
potentiation of aberrant transcriptional plasticity and increased drug seeking behaviors. Using a unique
combination of chromatin biochemistry, chemical biology, genome-wide and functional neurobiological
approaches, we plan to fully characterize the functions of histone dopaminylation, both in the context of normal
neuronal function and in ethologically valid rodent models of drug abuse; understanding these highly novel
molecular phenomena promises to provide new insights into the underlying mechanisms of drug addiction, and
aims to identify novel targets for the development of more effective therapeutics. Lastly, given the fundamental
role other monoaminergic systems (e.g., serotonin, norepinephrine) in addiction...

## Key facts

- **NIH application ID:** 10148742
- **Project number:** 5DP1DA042078-06
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ian S. Maze
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $508,500
- **Award type:** 5
- **Project period:** 2016-06-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148742

## Citation

> US National Institutes of Health, RePORTER application 10148742, Roles for histone monoaminylation in cocaine-induced transcriptional and behavioral plasticity (5DP1DA042078-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10148742. Licensed CC0.

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