# DAT-Psychostimulant mediated dopamine release increases macrophage IL-1beta production through NF-kB activation and inflammasome priming

> **NIH NIH R21** · DREXEL UNIVERSITY · 2021 · $195,625

## Abstract

DAT18-01. Abuse of stimulants, such as cocaine and methamphetamine, results in a variety of
serious health conditions, and drug abusers have poorer health outcomes than non-drug using,
demographically similar populations. In the central nervous system, the use of stimulants induces
neuroinflammation through a greater release of inflammatory factors and recruitment of additional
leukocytes. This predisposes drug abusers to a higher incidence of neuropsychiatric,
cerebrovascular and motor disorders, and can also exacerbate the neuropathogenic impact of
infection with HIV, HCV and a number of bacterial pathogens. The precise pathways by which
stimulants mediate these effects are not clear, but many of these effects could be induced by
drug-associated activation of specific inflammatory triggers such as NF- kB. However, direct links
between stimulants and these neuroinflammatory mechanisms have not been described. The
premise of this proposal is that dopamine acts as a common mechanism by which
stimulants activate myeloid cell NF-kB and thereby initiate or exacerbate
neuroinflammation. Use of all stimulants acutely increases CNS dopamine levels, exposing cells
in dopamine-rich brain regions to aberrantly high dopamine concentrations. Among these cell
populations are myeloid cells, such as perivascular macrophages and microglia, which are the
primary immune cells in the CNS. Our published research shows that acute exposure to elevated
dopamine increases myeloid production of inflammatory cytokines, such as IL-1b, IL-6, CXCL8
and CXCL10. Our preliminary data suggest that dopamine acts by activating the NF- kB pathway
and priming the NLRP3 inflammasome, a complex that regulates the release of IL-1b, a master
regulator of inflammation. The specific pathways mediating this effect are not clear, and therefore
these studies will generate detailed information about specific dopamine receptors, gene and
protein targets mediating dopamine activation of
NF-kB
and NLRP3 in human macrophages.
Determining the specific signaling mechanisms and genes involved in dopamine induced
increases in NF-kB activity will indicate pathways that could be targeted to ameliorate the
neuroinflammatory effects of stimulant use, significantly improving the long-term health outcomes
of stimulant users. The data developed in this proposal will serve as a basis for future projects
examining the modulation of the myeloid dopaminergic system as a therapeutic strategy for
limiting the increased incidence of neurologic disease and inflammation associated with drug
abuse. These projects will examine both novel effectors and the repurposing of existing
dopaminergic therapeutics to ameliorate inflammation in the stimulant abusing population.

## Key facts

- **NIH application ID:** 10129932
- **Project number:** 5R21DA049227-02
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Peter Jesse Gaskill
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $195,625
- **Award type:** 5
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129932

## Citation

> US National Institutes of Health, RePORTER application 10129932, DAT-Psychostimulant mediated dopamine release increases macrophage IL-1beta production through NF-kB activation and inflammasome priming (5R21DA049227-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10129932. Licensed CC0.

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