# The role of VMAT-2 in mediating the impact of HIV-1 protein Tat and methamphetamine on dopamine neurotransmission and behavior

> **NIH NIH F31** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2022 · $38,708

## Abstract

Project Summary
 Dysregulation of dopaminergic function due to the HIV-1 transactivator of transcription (Tat) protein has
been implicated in the progression of HIV-1 associated neurocognitive disorders (HAND). Tat mediates
increases in dopamine (DA) release and acts as a negative allosteric modulator for the dopamine transporter
(DAT). In addition to DAT, previous work has identified Tat as a negative allosteric modulator for the vesicular
monoamine transporter (VMAT-2). VMAT-2 functions to repackage DA into vesicles for subsequent release.
Inhibition of VMAT-2 causes dysregulation of DA neurotransmission which can lead to autooxidation of DA and
apoptosis. The psychostimulant methamphetamine (METH), in addition to Tat, inhibits VMAT-2 function. METH
is a highly abused psychostimulant among HIV-1 infected persons. Expression of the Tat protein has been shown
to potentiate METH induced neurotoxicity and behavior. Considering the respective interactions between Tat or
METH and VMAT-2, we hypothesize that the Tat and METH effects on extracellular DA and behavior are
mediated by VMAT-2. We will address this hypothesis by first, determining the role for VMAT-2 in mediating Tat-
induced increases in DA release (Tat alone). We will use fast scan cyclic voltammetry to quantify DA release in
Tat expressing mice. Specifically, we will profile the pharmacological response to a VMAT-2 inhibitor to
determine whether Tat expression alters VMAT-2 function. Second, we will use two different METH
administration models (acute and chronic) and profile the response to the VMAT-2 inhibitor as in the first aim.
Lastly, we will determine whether a VMAT-2 specific inhibitor attenuates Tat-potentiated METH-conditioned
place preference behavior. This will give insight whether VMAT-2 mediates Tat-potentiated METH behavior. The
findings from this proposal will provide key insight into the molecular mechanism by which Tat increases
extracellular DA and determine whether VMAT-2 is a suitable drug target for future therapeutic intervention in
the treatment of METH abuse in HIV-1 infected persons.
.

## Key facts

- **NIH application ID:** 10547890
- **Project number:** 1F31DA057163-01
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Sarah Elizabeth Davis
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,708
- **Award type:** 1
- **Project period:** 2023-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10547890

## Citation

> US National Institutes of Health, RePORTER application 10547890, The role of VMAT-2 in mediating the impact of HIV-1 protein Tat and methamphetamine on dopamine neurotransmission and behavior (1F31DA057163-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10547890. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*