# Interactive effects of Meth, HIV and cART on astrocyte/neuron function

> **NIH NIH R01** · RUSH UNIVERSITY MEDICAL CENTER · 2020 · $495,905

## Abstract

ABSTRACT
Despite long-term combined antiretroviral therapy (cART), HIV+ drug abusers experience more severe and
rapid progression of HIV-associated neurocognitive disorders (HAND). Methamphetamine (Meth) is a potent
stimulant, which is highly abused in the USA, and associated with chronic systemic inflammation.
Understanding the mechanism(s) by which Meth and HIV induce pathologies in the brain, whether and how
chronic cART alters astrocyte/neuron function in the CNS, and whether Math (or other stimulants) affects cART,
is critical for improving current, and developing new effective therapeutic strategies for treating Meth addiction
and its comorbid conditions with HIV/AIDS. The medial prefrontal cortex (mPFC) is one of the key regulators
of cognition and addiction; but it is profoundly altered following chronic Meth and HIV exposure in vivo with
disrupted dopamine (DA) neurotransmission and immune activation of astrocytes. Both human and laboratory
animal studies demonstrate that the mPFC dysregulation is significantly implicated in chronic Meth-induced
brain dysfunction, associated with euphoria, craving, drug-taking and relapse. Cumulating evidence also
indicates that both astrocytes and glutamatergic pyramidal neurons in the PFC are altered after chronic Meth
or HIV exposure. Chronic Meth in vivo induces astrocytic and neuronal plasticity that differs from changes
induced by acute Meth in vitro; but the underlying mechanism(s) of either one is not fully understood. In this
proposed study, we will elucidate a novel, trace amine-associated receptor 1 (TAAR1)-mediated mechanism,
by which acute Meth in vitro alters astrocyte activity; and determine alterations in this mechanism after Meth
self-administration (Meth-SA) followed by a withdrawal (that elicits drug-seeking), in HIV-1 transgenic (Tg) or
non-Tg rats. Moreover, we will also determine whether and how chronic cART in vivo affects functional activity
of mPFC astrocytes and neurons; and whether such cART effects are altered by Meth-SA in the context of
neuroHIV. Specifically, we will first define the mechanism by which chronic Meth in vivo alters astrocyte
function (Aim1). We then will determine the mechanism by which Meth/HIV impacting on mPFC astrocytes/
neurons (Aim2). Finally, we will identify chronic effects of cART (using a fixed-dose combination of abacavir,
dolutegravir and lamivudine) in vivo on mPFC astrocytes/neurons, and whether chronic Meth-SA alters them
(Aim3). To prove the fundamental base of this proposed research, we provide justification, related citations,
and preliminary data to support the Scientific Premise, Scientific Rigor, Relevant Biological Variables, and
Resource Authentication for this proposal. Outcomes from the proposed research will reveal the novel, TAAR1-
mediated mechanism that plays a key role in underlying the comorbid Meth/HIV impact, and chronic cART
effects, on altering astrocytes and pyramidal neurons in the mPFC. This will advance our understanding...

## Key facts

- **NIH application ID:** 9954051
- **Project number:** 5R01DA044552-04
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** XIU-TI HU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $495,905
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9954051

## Citation

> US National Institutes of Health, RePORTER application 9954051, Interactive effects of Meth, HIV and cART on astrocyte/neuron function (5R01DA044552-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9954051. Licensed CC0.

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