# Mechanisms Underlying TAAR1-induced Wakefulness and REM Sleep Suppression

> **NIH NIH R01** · SRI INTERNATIONAL · 2021 · $645,843

## Abstract

PROJECT SUMMARY
 Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor involved in the regulation of
dopaminergic, serotonergic and glutamatergic activity. TAAR1 agonists have anxiolytic, antidepressant-, and
antipsychotic-like properties in both rodent and non-human primates; TAAR1 agonists are in clinical trials for
schizophrenia and Parkinson’s disease psychosis. We have previously shown that TAAR1 agonists are wake-
promoting in mice, rats and, most recently, non-human primates, characterized the sleep/wake phenotype of
Taar1 knockout (KO) and overexpressing (OE) mice, and evaluated the effects of TAAR1 agonists on
sleep/wake in wildtype (WT), KO and OE mice. We also showed that two different TAAR1 agonists suppressed
REM sleep and reduced cataplexy in mouse models of narcolepsy, precisely the properties desirable in a
narcolepsy therapeutic. Having established TAAR1 agonists as potential novel treatments for narcolepsy, we
will now investigate the underlying in vivo neurobiology. In Taar1-LacZ mice, we will determine whether TAAR1
is expressed in monoaminergic, glutamatergic or other cell types and use the RNAscope technology to
determine endogenous Taar1 mRNA expression in WT and KO mice and rats. Since TAAR1 negatively
regulates dopaminergic (DA) neuronal activity in vitro, we will test the hypothesis that TAAR1 partial agonism
promotes wakefulness by modulating DA arousal systems. To address this hypothesis, we will assess
neuronal activity in the ventral tegmental area and dorsal raphe nuclei of DAT-ires-Cre mice using in vivo Ca2+
microendoscopy, and determine whether pretreatment with DA D1- and D2-receptor antagonists attenuates
TAAR1-mediated wake-promotion. Since serotonergic neurons are wake-active and REM-inactive and TAAR1
negatively regulates serotonergic neuronal activity in vitro, we will also test the hypothesis that TAAR1 partial
agonism promotes wakefulness by modulating serotonergic arousal systems. We will determine whether
TAAR1 partial agonists modulate the activity of DRN serotonergic neurons using in vivo Ca2+ microendoscopy
in Fev-Cre mice and assess whether blockade of serotonergic signaling attenuates the wake-promoting effects
of TAAR1 partial agonists. We have found that TAAR1 deletion elevates high-frequency gamma EEG activity,
suggesting that TAAR1 modulates cortical function. To determine whether TAAR1-mediated elevation of
gamma activity is conserved across species and specific to TAAR1, we will investigate basal sleep/wake
physiology and conduct quantitative EEG analyses in Taar1 KO and OE rats and Taar2-9 KO mice. Together,
these Aims will begin to establish the neural circuitry and mechanisms that underlie the efficacy of TAAR1
agonists.

## Key facts

- **NIH application ID:** 10170448
- **Project number:** 5R01NS103529-04
- **Recipient organization:** SRI INTERNATIONAL
- **Principal Investigator:** Thomas S Kilduff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $645,843
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170448

## Citation

> US National Institutes of Health, RePORTER application 10170448, Mechanisms Underlying TAAR1-induced Wakefulness and REM Sleep Suppression (5R01NS103529-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10170448. Licensed CC0.

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