# Stimulant-induced excitatory and inhibitory dopamine receptor signaling and trafficking

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $701,995

## Abstract

Project Summary
The dopamine system plays a major role in the pathogenesis of substance use disorders. Stimulant drug use
and abuse lead to several dopaminergic alterations that contribute to the complex behavior associated with the
formation of addiction. A single acute exposure to a stimulant drug can trigger receptor internalization as an early
synaptic adaptation mechanism to high dopamine concentrations. These mechanisms have been shown to affect
neuroimaging outcomes, specifically positron emission tomography (PET), which has revealed paradoxically
long reductions in dopamine D2/D3 receptor availability after stimulant-induced dopamine release. To date, we
still have a limited understanding of the timeline of dopamine receptor internalization and recovery with repeated
drug exposure and how these adaptation mechanisms affect whole-brain signaling of both excitatory D1 and
inhibitory D2-type receptors. This study aims to address this knowledge gap by characterizing how two classes
of stimulant drugs (amphetamine and methylphenidate) modulate dopamine receptor subtype signaling and
receptor trafficking over time. Using state-of-the-art simultaneous PET and functional magnetic resonance
imaging (fMRI) methodology in non-human primates, the timescales of amphetamine-induced receptor
internalization and recycling will be established using repeated amphetamine administrations. Targeted
dopaminergic blocking drugs will be paired with amphetamine to determine how the balance between excitatory
D1 and inhibitory D2 receptor signaling and trafficking is modulated over time. The effects of repeated
amphetamine will then be compared to those of methylphenidate to assess varying levels of dopamine surges
and differential mechanisms of action across these two stimulant drugs. Overall, this study will unravel brain-
wide molecular and functional changes due to repeated stimulant drug exposure by imaging the timescales of
dopamine receptor trafficking in the living brain in a translational animal model. The results will elucidate the role
of dopamine D1 and D2-type receptor adaptations, thereby providing important insight into the neurobiological
mechanisms involved in repeated stimulant drug use relevant for initiating and eventually preventing drug
sensitization and addiction.

## Key facts

- **NIH application ID:** 10930936
- **Project number:** 5R01DA056488-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Christin Y. Sander
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $701,995
- **Award type:** 5
- **Project period:** 2023-09-30 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930936

## Citation

> US National Institutes of Health, RePORTER application 10930936, Stimulant-induced excitatory and inhibitory dopamine receptor signaling and trafficking (5R01DA056488-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10930936. Licensed CC0.

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