# Consequences of HDAC2 inhibition in VTA-NAc circuitry

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $509,266

## Abstract

ABSTRACT
Bipolar disorder is a common psychiatric disease with few treatment options and no cure. One of the most
commonly prescribed medications for treatment of acute mania and mood stabilization is the anticonvulsant
drug, valproate (VPA; trade name Depakote). This medication has been used since the mid-1990s, however not
everyone responds equally to VPA in terms of therapeutic efficacy and it can produce multiple, often severe side
effects. Moreover, VPA has a variety of molecular targets and it is unclear which targets are therapeutically
relevant. Better understanding of the molecular mechanisms that normalize mania in response to VPA could
lead to more targeted treatments in the future which produce a higher therapeutic response with less side effects.
In the first funding cycle of this grant, we discovered that the therapeutic actions of VPA appear to occur via it’s
inhibition of a protein called histone deacetylase 2 (HDAC2) specifically in a part of the brain that contains a
large number of dopaminergic neurons, the ventral tegmental area (VTA). HDAC2 is involved in the regulation
of gene expression on a wide scale, so while the inhibition of this protein is perhaps more targeted than VPA
treatment, it is still advantageous for us to identify the important genes who’s expression is changed as a result
of HDAC2 inhibition in the VTA. To identify these targets, we will first determine which genes are normally bound
by HDAC2 and what changes to histone acetylation occur in response to HDAC2 inhibition in the VTA using two
animal models that have a behavioral profile that is strikingly similar to human mania and increased dopaminergic
activity in the VTA. We will then determine which gene and protein expression changes occur with HDAC2
inhibition and combine these results with those of the first Aim, and our prior results, to determine the particular
proteins that might be likely therapeutic candidates. In Aim 3 we will then determine the impact of HDAC2
inhibition and direct target genes of HDAC2 on VTA dopaminergic activity and signaling in our mouse models to
help identify the mechanisms by which HDAC2 target genes might normalize human mania. Taken together, this
study will help us to identify novel therapeutic targets and their mechanism of action for the treatment of bipolar
disorder.

## Key facts

- **NIH application ID:** 10875522
- **Project number:** 5R01MH106460-08
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Colleen A McClung
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $509,266
- **Award type:** 5
- **Project period:** 2016-04-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875522

## Citation

> US National Institutes of Health, RePORTER application 10875522, Consequences of HDAC2 inhibition in VTA-NAc circuitry (5R01MH106460-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10875522. Licensed CC0.

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