# Extracellular vesicles, meth relapse and sex differences

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $569,253

## Abstract

The abuse of the potent psychostimulant methamphetamine (meth) continues to pose a significant threat not
just in the US but also globally. A significant attribute associated with chronic meth induced brain dysfunction is
inflammation includes activation of glial cells such as astrocytes and microglia that play a crucial role in
modulating inflammation including glutamate excitotoxicity at the synapse. Mounting evidence suggests that
inflammation and alterations in glutamate neurotransmission are two novel pathways associated with the
pathophysiology in mood disorders. Notably, this cross talk between neurons and glial cells is mediated by
extracellular vesicles (EVs) which are emerging as key players in regulating brain function. Chronic meth
dependent individuals, including those abstinent and then relapse, display significant behavioral (mood)
alterations such as psychosis. A significant gap in knowledge is understanding how meth-induced inflammation
perturbs glutamatergic physiology which subsequently impair EV dynamics and exacerbates relapse. Adding
another layer of importance is emerging studies showing a role for sex differences with females progressing
more quickly to regular use of meth as well as greater dependence and higher relapse rates. Given the lack of
studies elucidating the role of EVs with meth relapse between the sexes, our proposed studies are well poised
to address this important knowledge gap. Accordingly, the overarching goal of this proposal is to examine the
role of EVs in the damaging effects of meth between the sexes using drug-triggered reinstatement (relapse) of
extinguished intravenous meth self-administration in rats. Based on our recent preliminary studies with females
showing higher inflammation, enhanced glutamatergic alterations, and significantly higher drug-triggered
reinstatement (i.e., meth seeking), we hypothesize that EV biogenesis, release, and associated cargo are more
impacted in females than males. Using an array of complementing behavioral, molecular, and biochemical
approaches in a “gold standard” preclinical model or reinstatement we will : determine how the anti-inflammatory
drug ibudilast alters dynamics of EV release, biogenesis, and associated cargo between the sexes (Aim1);
Characterize role of EVs isolated from the sexes on synaptodendritic damage (Aim 2 and) test meth induced
changes in EV-associated surface proteins between the sexes (Aim 3). These studies will break new ground and
importantly provide novel proof of concept studies which will further serve as a prelude to future basic research
on developing EVs as sex-specific medication development for treating meth addiction.
.!

## Key facts

- **NIH application ID:** 10200728
- **Project number:** 5R01DA046852-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Rick A Bevins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $569,253
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200728

## Citation

> US National Institutes of Health, RePORTER application 10200728, Extracellular vesicles, meth relapse and sex differences (5R01DA046852-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200728. Licensed CC0.

---

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