# Molecular mechanisms: Dysregulation of monoamine transporters by HIV-1 Tat and cocaine

> **NIH NIH R01** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2020 · $515,165

## Abstract

Perturbation of dopaminergic transmission is implicated as a risk factor of HIV-1 associated
neurocognitive disorders (HAND). Dopaminergic system plays a causal role in drug rewarding
and modulation of the brain function including cognition. Prefrontal cortex is an important brain
region for higher cognitive function, where norepinephrine transporter (NET) is the primary
mechanism of homeostatic regulation of stable synaptic dopaminergic tone. HIV-1 Tat protein
and cocaine synergistically increase synaptic dopamine levels, thereby producing
neurocognitive impairment. Our initial findings show that in vitro exposure to recombinant Tat1-86
inhibits dopamine and norepinephrine reuptake by dopamine transporter (DAT) and NET and
Tat binds to DAT and NET through a direct protein-protein interaction. We have demonstrated
that Tat-induced inhibition of DAT function is mediated by binding to allosteric binding site(s) on
DAT, not by interacting with the DA uptake site. Accordingly, attenuating Tat binding to DAT
would be expected to have minimal influence on physiological DA transport. Indeed, our recent
findings show that a novel quinazoline series of allosteric modulators decrease cocaine potency
for inhibition of DA uptake and attenuate Tat-induced inhibition of DA reuptake and cocaine
binding by DAT. We hypothesize that Tat, via the unique allosteric modulatory sites, perturbs
the DAT and NET regulatory network that normally sustains concentrative DA or NE transport
and potentiates cocaine’s effect on DAT and NET, resulting in DA/NE-linked neuropsychiatric
dysfunction prominently featured in HAND. We will (Aim 1) Identify the binding sites for Tat in
human NET, and explore allosteric modulation of this transporter by Tat and cocaine; (Aim 2)
determine the pathogenic role of DAT/NET-mediated dopaminergic transmission in inducible Tat
transgenic mice by assessment of Fast-scan cyclic voltammetry and whole cell patch clamp
recording; and (Aim 3) perform proof of concept studies using novel allosteric modulators to
establish their potential for therapeutic application in HAND using integrated computational
modeling, pharmacological, and behavioral approaches. Our long-term goal is to explore new
ways to target DAT/NET for therapeutic interventions to improve neurocognitive dysfunction of
HAND in concurrent cocaine abusers.

## Key facts

- **NIH application ID:** 9856421
- **Project number:** 5R01DA035714-08
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Jay P. McLaughlin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $515,165
- **Award type:** 5
- **Project period:** 2013-07-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856421

## Citation

> US National Institutes of Health, RePORTER application 9856421, Molecular mechanisms: Dysregulation of monoamine transporters by HIV-1 Tat and cocaine (5R01DA035714-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9856421. Licensed CC0.

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