# Striatal Mechanisms of Dyskinesia and Impulse Control in Parkinson’s Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $398,618

## Abstract

Project Abstract
The motor symptoms of Parkinson’s Disease (PD) are frequently treated with dopamine replacement therapies,
such as the dopamine precursor levodopa or dopamine receptor agonists. While very effective for some of the
cardinal motor features, these medications can cause two major complications: levodopa-induced dyskinesia
(LID) and impulse control disorder (ICD). LID consists of drug-induced abnormal involuntary movements, and is
closely associated with levodopa. ICD manifests as a syndrome of impulsive and/or compulsive behaviors, such
as pathological gambling, hypersexuality, or binge eating, and is closely associated with dopamine D2/3R
agonists. Little is known about the synaptic or circuit mechanisms of either disorder, though substantial progress
has been made on LID through the use of animal models of PD/LID. In our prior work, we have found that a
subset of striatal direct pathway medium spiny neurons achieve high levodopa-evoked firing rates in vivo, which
correlate with and cause dyskinesia in the mouse model. Other intermingled direct pathway neurons correlate
with the therapeutic effects of levodopa. We have also recently developed a mouse model of PD/ICD, based on
a delay discounting task and administration of the dopamine agonist pramipexole, which will permit more
mechanistic studies. In this proposal we will explore some cellular and circuit mechanisms of LID and ICD, using
in vivo and ex vivo electrophysiology, optogenetics, and chemogenetics in mouse models. This proposal aims
to (1) test whether local striatal inhibitory synapses are altered in and contribute to LID, (2) determine whether
extrinsic inhibitory synapses from the globus pallidus to the striatum are altered in and contribute to LID, and (3)
begin to explore the striatal mechanisms of ICD. These studies will build on our prior work in LID to unravel its
cellular mechanisms, but also determine if ICD is mediated by similar or distinct processes. Together, these
studies will lay the groundwork for new PD treatments that harness the benefits of dopamine without the
complications.

## Key facts

- **NIH application ID:** 10735816
- **Project number:** 2R01NS101354-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Alexandra Nelson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $398,618
- **Award type:** 2
- **Project period:** 2018-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10735816

## Citation

> US National Institutes of Health, RePORTER application 10735816, Striatal Mechanisms of Dyskinesia and Impulse Control in Parkinson’s Disease (2R01NS101354-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10735816. Licensed CC0.

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