The trace amines (TAs), endogenous amino acid metabolites previously considered "false neurotransmitters," have recently been shown to act as endogenous ligands for trace amine-associated receptor 1 (TAAR1). TAAR1 is a G protein-coupled receptor that modulates dopaminergic, serotonergic and, possibly, glutamatergic activity. In papers recently published in Molecular Psychiatry and Biological Psychiatry with scientists from F. Hoffmann-LaRoche, we describe novel, brain-penetrable TAAR1 agonists with pro-cognitive, antidepressant- and antipsychotic-like properties, suggesting TAAR1 as a novel target for the treatment of neuropathological disorders. We also show that TAAR1 partial agonism causes a dose- dependent increase in wakefulness and decreases in NREM and REM sleep, indicating that this receptor activates an endogenous wake-promoting system. In the present proposal, we will determine whether endogenous TAAR1 tone contributes to the normal distribution of sleep and wakefulness, the homeostatic response to sleep deprivation, and the response to endogenous and exogenous compounds known to promote wakefulness. First, we will determine whether TAAR1 signaling is involved in the maintenance of daily sleep- wake patterns and the homeostatic regulation of sleep in TAAR1 null mutant mice. In the context of these studies, we will determine whether the wake-promoting effects of TAAR1 agonists studied to date are absent in these mice. Next, we will determine the consequences of overexpression of TAAR1 on the normal distribution of sleep and wakefulness and the homeostatic response to sleep deprivation. Lastly, we will determine whether TAAR1 signaling is necessary for the wake-promoting effects of the stimulant caffeine and the wake- promoting therapeutic modafinil (Provigil(R)) and the endogenous wake-promoting neuropeptide, hypocretin-1 (orexin-A). The results obtained will advance our understanding of the interaction of TAAR1 with wakefulness- promoting systems in the brain, and will likely impact the development of pharmacotherapies directed toward this novel target for the treatment of sleep/wake and other neural disorders.

Public Health Relevance

We have recently described novel, brain-penetrable agonists for Trace Amine-associated Receptor 1 (TAAR1) in papers published in Molecular Psychiatry and Biological Psychiatry with scientists from F. Hoffmann-LaRoche, These compounds have pro-cognitive, antidepressant- and antipsychotic-like properties, suggesting TAAR1 as a novel target for the treatment of neuropathological disorders. We also show that TAAR1 partial agonism causes a dose-dependent increase in wakefulness and decreases in NREM and REM sleep, indicating that this receptor activates an endogenous wake-promoting system. In the present proposal, we will determine whether endogenous TAAR1 tone contributes to the normal distribution of sleep and wakefulness, the homeostatic response to sleep deprivation, and the response to endogenous and exogenous compounds known to promote wakefulness. The results obtained will advance our understanding of the interaction of TAAR1 with other brain systems, and will likely impact the development of pharmacotherapies directed toward this novel target for the treatment of sleep/wake and other neural disorders.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS082876-02
Application #
8725760
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
He, Janet
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Sri International
Department
Type
DUNS #
City
Menlo Park
State
CA
Country
United States
Zip Code
94025