# Illuminating the Mechanisms of Dopamine Neurotransmission in the Striatum

> **NIH NIH F32** · UNIVERSITY OF COLORADO DENVER · 2020 · $67,446

## Abstract

PROJECT SUMMARY
Striatal dopamine (DA) transmission is crucial for movement, motivation and reward, but is critically disrupted
in neurodegenerative, neuropsychiatric and substance abuse disorders. Despite the importance of DA
signaling in both health and disease, its mechanisms remain poorly understood. Striatal DA receptors are often
located outside of synapses and striatal DA release sites are not always associated with post-synaptic
structures. These observations have led to the belief that DA signaling occurs by ‘volume transmission’
whereby low concentrations of DA diffuse from release sites and non-selectively activate receptors across a
large sphere of influence. However, recent evidence has challenged this concept. Our previous work has
demonstrated that DA release drives the rapid activation of D2 receptors and D2 receptor-mediated inhibitory
post-synaptic currents (D2-IPSCs) in striatal medium spiny neurons (MSNs). Furthermore, others have shown
that striatal DA release only occurs at a small proportion of DA varicosities (20-30%) which requires
specialized machinery (active zones) which typically enables highly precise forms of neurotransmission. These
findings suggest that striatal DA signaling occurs in a spatially-restricted manner. Consistent with this idea,
recent work has demonstrated that DA release occurs from highly localized ‘hotspots’ detected with
genetically-encoded fluorescent DA sensors. Considering the high density of diverse inputs which are
integrated in the striatum, the spatial organization DA signaling is critical for striatal output. However, the
organization of DA release sites and post-synaptic receptors remains unclear. Furthermore, drugs of abuse
(e.g. cocaine) increase the spread of DA signaling by preventing its uptake. Considering this effect, the
contribution of uptake to DA signaling requires further elucidation.
This study will utilize a novel approach combining high resolution, two-photon microscopy of a genetically-
encoded fluorescent DA sensor, with synaptic electrophysiology to: (1) definine the dynamics and organization
of DA neurotransmission in the dorsal striatum; and (2) determine the contribution of diffusion and uptake to
DA signaling. These experiments will test the hypothesis that that DA transmission occurs at specialized
‘synapse-like’ structures in a point-to-point manner. Better illumination of DA signaling and its associated
microarchitecture will allow better understanding of pathological changes which occur at DA synapses
underlying substance abuse and drug addiction.

## Key facts

- **NIH application ID:** 9991475
- **Project number:** 1F32DA051135-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Andrew Gregory Yee
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 1
- **Project period:** 2020-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991475

## Citation

> US National Institutes of Health, RePORTER application 9991475, Illuminating the Mechanisms of Dopamine Neurotransmission in the Striatum (1F32DA051135-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9991475. Licensed CC0.

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