# Pharmacological modulation of striatal physiology and repetitive behaviors by M4 PAMs

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2022 · $396,250

## Abstract

Project Summary / Abstract
Repetitive behaviors are commonly observed in disorders such as Obsessive-Compulsive Disorder (OCD),
Tourette’s Syndrome (TS), and Autism Spectrum Disorders (ASDs). These behaviors can have profound
negative effects on patients’ lives and can impair their ability to learn, carry out social interactions, and adapt to
changing environments. While selective serotonin reuptake inhibitors, antipsychotics, and behavioral therapy
are moderately effective in treating these symptoms, many patients are refractory to these therapies and there
is a critical need to identify better treatment strategies to help patients with these disabling symptoms. The
striatum is a brain region that plays a key role in integrating information from numerous brain structures and is
essential to modulating habitual and goal-directed behaviors. Converging clinical and preclinical data suggest
that hyperactive dopaminergic and glutamatergic neurotransmission through specific circuits in the striatum
may represent common mechanistic underpinnings of abnormal repetitive behaviors. Interestingly, extensive
studies from our lab and others have found that the M4 subtype of muscarinic acetylcholine receptor can exert
powerful modulatory control over striatal dopaminergic and glutamatergic transmission, raising the possibility
that selective activators of M4 could reverse pathological changes that may give rise to repetitive behaviors.
Here we provide preliminary data demonstrating that M4 PAMs can reduce excessive grooming in SAPAP3 KO
mice (a genetic mouse model that displays a repetitive over-grooming phenotype). This could provide a
breakthrough in identifying a novel approach for treatment of disabling symptoms that are resistant to available
therapies. We hypothesize that repetitive behaviors in multiple animal models displaying repetitive grooming
are associated with hyperactive glutamate and dopamine release in the striatum, and that M4 PAM treatment
can reduce repetitive behaviors by normalizing these forms of neurotransmission. We will test this hypothesis
through a series of electrophysiological and behavioral studies using a combination of genetically modified
mice, optogenetic approaches, and novel pharmacological tools. These studies will provide important
information regarding the physiological role of M4 receptors in regulating basal ganglia function and will
elucidate the therapeutic potential of M4 PAMs in providing relief from repetitive behaviors.

## Key facts

- **NIH application ID:** 10320960
- **Project number:** 5R01MH122545-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Daniel J Foster
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2021-01-01 → 2022-07-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320960

## Citation

> US National Institutes of Health, RePORTER application 10320960, Pharmacological modulation of striatal physiology and repetitive behaviors by M4 PAMs (5R01MH122545-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320960. Licensed CC0.

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