# Mechanisms of opiate drug-HIV-induced neurodegeneration

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $355,296

## Abstract

Opiate abuse potentiates the neuropathogenesis of HIV by synergistically increasing dendritic pathology
(varicosity formation, beading, fragmentation, pruning), while promoting additive dendritic spine losses
(plasticity). Behavioral deficits in spatial and non-spatial memory tasks are accompanied by synaptic losses
and dendritic pathology preceding neuron death, suggesting that neuronal injury and reduced synaptic
connectivity underlie the ability of opioids to aggravate HIV-associated neurological disorders (HAND). We
have found that phenotypically distinct subpopulations of hippocampal CA1 interneurons appear to be highly
sensitive to Tat ± opiates, and disruptions to these interneuron subpopulations may contribute, in part, to
pyramidal cell dysfunction/injury. These findings represent a fundamental shift in our understanding of opioid
drug action and propel the grant in novel directions. We hypothesize that opiates and HIV-induced
hippocampal behavioral dysfunction is caused by disruptions to synaptic function and organization in
vulnerable neuronal subpopulations that disrupt specific neural networks within the hippocampus. Aim 1 will
characterize the neurophysiologic events underlying opioid and HIV-dependent neuronal dysfunction and injury
in hippocampal CA1 pyramidal cells in whole-cell, patch-clamp recordings of CA1 pyramidal cells. Alterations
in long-term potentiation and depression will be explored, as will deficits in subthreshold postsynaptic
potentials in response to opiates and Tat. During patch-clamp recordings, neurons will be biocytin-filled and
subsequently analyzed via 3D-reconstruction for dendritic pathology and spine density. Aim 2 will determine
how vulnerable subsets of MOR-expressing CA1 interneurons exacerbate opiate and HIV-1-induced
hippocampal dysfunction, neuronal injury, and disrupt network function. Tat tg mice will be crossed with
MORfloxed;VGAT-Cre mice, which lack MOR+ CA1 interneurons. We will also determine how Tat and opiates
affect synaptic processing and network function in CA1 by examining the integration of synaptic inputs by
imaging genetically encoded-voltage indicators (GEVIs) selectively expressed in CA1 pyramidal neurons. Aim
3 will identify the neurophysiologic mechanisms underlying opiate and infectious HIV-1/HIV protein-induced
neuronal dysfunction and injury in human hippocampal neurons. Opiate and Tat-induced neurophysiological
and structural deficits will be correlated with deficits seen in Tat mice assessed in Aims 1 and 2. Our long-term
goal is to define the mechanisms by which opiate drug abuse exacerbates neurodegenerative and functional
defects, and to identify key underlying events that could be targeted therapeutically.

## Key facts

- **NIH application ID:** 9838164
- **Project number:** 5R01DA018633-14
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Kurt F Hauser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,296
- **Award type:** 5
- **Project period:** 2005-09-30 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838164

## Citation

> US National Institutes of Health, RePORTER application 9838164, Mechanisms of opiate drug-HIV-induced neurodegeneration (5R01DA018633-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9838164. Licensed CC0.

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