# Vagus nerve stimulation increases basal dopamine levels in the brain to decrease methamphetamine-mediated responses

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2023 · $541,679

## Abstract

Abstract
The long-term goal of this study is to determine how vagus nerve stimulation (VNS) regulates basal dopamine
transmission and methamphetamine regulation of dopamine neurons. Methamphetamine abuse is a major public
health issue around the world, yet there are no effective pharmacotherapies for the treatment of methamphetamine
addiction. Methamphetamine is a potent psychostimulant that increases extracellular dopamine levels by targeting
the dopamine transporter (DAT) in the midbrain and striatum. In the previous cycle of this grant, we shown that
methamphetamine competes with the DAT-mediated dopamine uptake, increases dopamine efflux via the DAT,
increases the DAT mediated inward depolarizing current leading to increased firing activity of dopamine neurons.
Methamphetamine increases Ca2+ levels in the dopamine neurons that enhances both action potential dependent
and independent dopamine release (i.e., dopamine efflux). We also found that neuronal depolarization induces
DAT internalization leading to decreased dopamine and methamphetamine uptake. Multiple studies have shown
that VNS increases dopamine levels in the midbrain region and reduces cocaine seeking behavior, albeit with an
unknown mechanism via a multi-synaptic connection between vagus nerve and midbrain region. We found that
optogenetic stimulation of vagal sensory neurons innervating the upper gastrointestinal tract depolarizes
dopamine neurons and increases basal firing activity of midbrain dopamine neurons lasting for at least 30 minutes.
Histological analyses revealed a reduction in somatodendritic DAT in the c-fos positive neurons. These data are
consistent with our previous report showing neuronal depolarization induces DAT internalization, that can reduce
the efficacy of methamphetamine regulation of dopamine transmission. Our preliminary data also revealed that
optogenetic VNS increases extracellular dopamine levels that does not reach ceiling levels, but it reduces the
methamphetamine stimulation of dopamine neurons, by depolarizing dopamine neurons, reducing DAT levels.
These preliminary data and the literature support the overarching hypothesis that VNS increases basal dopamine
levels by depolarizing dopamine neurons, reducing DAT levels, and decreasing methamphetamine-stimulation of
dopamine transmission thereby attenuating methamphetamine’s behavioral and cellular responses. Our proposed
studies will determine the underlying cellular mechanism for VNS-regulation of dopamine transmission and
methamphetamine-induced responses.

## Key facts

- **NIH application ID:** 10648045
- **Project number:** 1R01DA058143-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Habibeh Khoshbouei
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $541,679
- **Award type:** 1
- **Project period:** 2023-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10648045

## Citation

> US National Institutes of Health, RePORTER application 10648045, Vagus nerve stimulation increases basal dopamine levels in the brain to decrease methamphetamine-mediated responses (1R01DA058143-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10648045. Licensed CC0.

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