# Selective muscarinic receptor antagonists as therapeutics in dystonia

> **NIH NIH F31** · EMORY UNIVERSITY · 2020 · $45,520

## Abstract

Dystonia is a movement disorder characterized by muscle contractions that cause debilitating twisting
movements and postures. DYT1 dystonia, the most common inherited dystonia, is a severe form of
generalized dystonia. DYT1 dystonia is caused by a mutation in the TOR1A gene, resulting in a glutamic acid
deletion in the TorsinA protein. Despite the identification of a causal mutation, our understanding of the
mechanisms that lead to abnormal movements is incomplete. This limited understanding of pathological
mechanisms likely explains, in part, why there are few therapeutics available to treat the disorder. The
preferred oral therapeutic for dystonia is the non-selective muscarinic antagonist trihexyphenidyl (THP). While
THP is an effective treatment for many patients, its utility is limited by dose-limiting side effects. To date, the
mechanism of action of THP in DYT1 dystonia is unknown. One clue to THP’s therapeutic mechanism is the
fact that dopamine (DA) dysfunction in the basal ganglia has been consistently implicated in many forms of
dystonia. Humans with DYT1 have normal striatal tissue DA but have abnormal DA metabolite ratios. Mice
harboring the human DYT1-causing mutation also have normal striatal tissue DA, but reduced extracellular DA
in the striatum. This evidence suggests that striatal DA release is reduced in DYT1 mice and humans.
Importantly, preliminary data collected in our lab shows that THP effectively enhances striatal extracellular DA
concentrations. However, the exact muscarinic receptor subtypes responsible for this effect are unknown. This
is a critical piece of information for developing new treatments for dystonia, without the adverse side effect
profile of THP. The purpose of this proposal is to determine the muscarinic receptor subtype(s) responsible for
the DA-enhancing effect of THP and the improvement of motor symptoms in DYT1 dystonia.

## Key facts

- **NIH application ID:** 9836896
- **Project number:** 5F31NS103363-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Anthony M Downs
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2018-02-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836896

## Citation

> US National Institutes of Health, RePORTER application 9836896, Selective muscarinic receptor antagonists as therapeutics in dystonia (5F31NS103363-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9836896. Licensed CC0.

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