# Elucidating Ih Biophysical Epigenetic Modifications in VTA Dopaminergic Neurons after Contingent and Non-Contingent Cocaine Administration

> **NIH NIH R16** · UNIVERSITY OF PUERTO RICO MED SCIENCES · 2024 · $141,272

## Abstract

ABSTRACT
The ventral tegmental area (VTA) is a key CNS region involved in the reward and reinforcement
of natural substances and drugs, such as cocaine. Hyperpolarization-activated cation current (Ih)
is a key participant in the fundamental intrinsic properties of dopaminergic (DA) neurons of the
VTA. The ion channels that carry Ih are comprised of HCN subunits, predominantly the HCN2 in
the VTA. Alteration of Ih due to drug exposure has been shown after cocaine sensitization (CS).
This change in Ih may be a common physiological mechanism in central reward/reinforcement
pathways that contributes to addiction. Epigenetic mechanisms like histone deacetylation are
responsible for some crucial neuronal changes that occur following chronic drug administration.
This project will study the epigenetic regulation of the Ih function during the development of CS
and on the Intermittent access self-administration (IntA) model. The IntA in our opinion better
simulates human drug consumption. The specific aims will include: 1) To investigate the VTA
epigenomic profile after CS, IntA and Histone Deacetylase inhibitor (HDACi); 2)
Electrophysiological examination of Ih in VTA DA neurons after CS, IntA and HDACi; 3) To
measure changes in HCN2 subunits in the VTA after CS, IntA and HDACi; 4) To investigate if in
vivo shRNA targeting HDAC2 alters the development of CS, IntA and Ih properties of VTA DA
neurons. Examination of cocaine-induced epigenetic changes in the VTA can provide key
information about neuroadaptations that occur during the development of addiction. The reversal
of these epigenetic modifications by histone deacetylase inhibition might provide possible
avenues for therapeutic pharmacological intervention.

## Key facts

- **NIH application ID:** 10851998
- **Project number:** 5R16GM145475-03
- **Recipient organization:** UNIVERSITY OF PUERTO RICO MED SCIENCES
- **Principal Investigator:** CARLOS A JIMENEZ-RIVERA
- **Activity code:** R16 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $141,272
- **Award type:** 5
- **Project period:** 2022-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851998

## Citation

> US National Institutes of Health, RePORTER application 10851998, Elucidating Ih Biophysical Epigenetic Modifications in VTA Dopaminergic Neurons after Contingent and Non-Contingent Cocaine Administration (5R16GM145475-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10851998. Licensed CC0.

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