# Dissecting Modes of Dopamine Transmission and Their Roles in Reward Related Behaviors

> **NIH NIH F32** · UNIVERSITY OF COLORADO DENVER · 2024 · $74,284

## Abstract

PROJECT SUMMARY
Striatal dopamine serves a critical role in motivation, reward learning, and decision making. Aberrations in
dopamine transmission are thought to underlie a variety of neuropsychiatric diseases and substance abuse
disorders. Yet, despite dopamine’s prominent role in behavior and disease, mechanistic understanding of how
transmission occurs at the subcellular level has remained limited due to methodological restrictions. Structural
data shows that dopamine neurons form extensively arborized axons with sparse release sites (varicosities) that
are often unassociated with postsynaptic receptors. Combined with early methods of measuring dopamine, these
findings have led to the belief that dopamine signals primarily through ‘spillover’ transmission, characterized by
slow changes (hundreds of milliseconds or more) in low concentrations of dopamine (<1 µM) over a broad radius
(~10 µm). However, accumulating evidence has recently challenged this notion. Imaging of fluorescent dopamine
sensors has revealed the presence of highly localized dopamine ‘hotspots.’ Further, electrophysiological
recordings show that endogenous dopamine release rapidly modulates postsynaptic targets and is only
precluded by concentrations far higher than those observed in spillover release. These data suggest that
dopamine signaling can also occur through tightly coupled ‘synaptic’ transmission, characterized by rapid
changes (milliseconds) in high concentrations of dopamine (10-100 µM) that are spatially restricted (~ 3 µm).
The stark difference in spatiotemporal structure between spillover and synaptic transmission suggests that these
two modes mediate distinct functions. Yet, little is known about how spillover and synaptic dopamine
transmission are regulated or how these two forms of transmission inform healthy and diseased behaviors.
This study will implement an innovative combination of synaptic electrophysiology and behavioral assays with a
battery of perturbations to dopamine release to determine: (1) whether spillover and synaptic transmission occur
through independent or intertwined mechanisms of release, and (2) whether these two forms of transmission
serve distinct functions in reward behaviors. Together, these experiments will test the hypothesis that synaptic
and spillover dopamine release are two independently regulated forms of transmission with distinct behavioral
functions. By illuminating the microarchitecture of dopamine release, this work will lay a new framework for
understanding how dopamine transmission shapes reward behaviors critical to both health and addiction.

## Key facts

- **NIH application ID:** 10900150
- **Project number:** 1F32DA060556-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Matthew M McGregor
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,284
- **Award type:** 1
- **Project period:** 2024-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900150

## Citation

> US National Institutes of Health, RePORTER application 10900150, Dissecting Modes of Dopamine Transmission and Their Roles in Reward Related Behaviors (1F32DA060556-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10900150. Licensed CC0.

---

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