The goal of this proposal is to determine whether ligands for Trace Amine-associated Receptor 1 (TAAR1) are wake-promoting and pro-cognitive in non-human primates as we have found in laboratory rodents. Recent identification of selective agonists for TAAR1 that exhibit pro-cognitive, antidepressant- and antipsychotic-like properties in both rodent and non-human primates suggest TAAR1 is a novel target for the treatment of neuropsychiatric disorders. In collaboration with scientists from F. Hoffmann-La Roche, we have described brain-penetrable compounds with high potency and selectivity at mouse, rat, monkey and human TAAR1. Moreover, we showed that TAAR1 agonism causes a dose-dependent increase in wakefulness in rats and have replicated this effect in mice. Given the widespread occurrence of sleep disorders, we will further test the hypothesis that TAAR1 agonism is a novel therapeutic pathway to promote wake and enhance cognition. First, we will determine whether TAAR1 agonism promotes wakefulness in Cynomolgus macaques under conditions of both high and low sleep pressure. Although TAAR1 agonists increase vigilance in rodents, these animals are nocturnal and have polyphasic sleep/wake cycles in comparison to the consolidated periods of sleep and wakefulness characteristic of both humans and non-human primates. Implementation of EEG recording in these studies will enable us to determine the effects of TAAR1 agonism on NREM and REM sleep and to conduct quantitative EEG (qEEG) analysis to assess the effects of these compounds on EEG frequencies associated with cognition such as gamma oscillations. Next, we will test these compounds for their ability to improve working memory functions in macaques under baseline and sleep deprivation conditions. Working memory function is dependent on prior sleep history and subject to decline in aging, stress and in diseases such as schizophrenia and Alzheimer's disease. We have shown previously that TAAR1 agonists improve executive functions (e.g., response inhibition, planning) in non-human primates and in a rodent PCP-induced deficit model, however, this represents only one cognitive domain that can be affected in sleep disorders. Simultaneous assessment of behavior and qEEG in macaques performing the working memory task will enable investigation of cognitive function at both behavioral and electrophysiological levels. The results of these studies will aid in establishing TAAR1 agonism as a novel mechanism to enhance wakefulness and cognition in humans.

Public Health Relevance

Recent identification of selective agonists for the Trace Amine-associated Receptor 1 (TAAR1) that exhibit pro-cognitive, antidepressant- and antipsychotic-like properties in both rodent and non-human primates suggest TAAR1 is a novel target for the treatment of neuropsychiatric disorders. In papers recently published with scientists from F. Hoffmann-La Roche, we describe brain-penetrable compounds with high potency and selectivity at mouse, rat, monkey and human TAAR1. Importantly, we showed that these TAAR1 agonists dose-dependently increase wakefulness in rats and we have recently replicated this effect in mice. Given the widespread occurrence of sleep disorders, the goal of our proposal is to further test the hypothesis that TAAR1 agonism is a novel therapeutic pathway to promote wake and enhance cognition in non-human primates that exhibit the consolidated periods of sleep and wakefulness characteristic of human sleep.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS085757-01A1
Application #
8775141
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
He, Janet
Project Start
2014-08-15
Project End
2016-07-31
Budget Start
2014-08-15
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$476,989
Indirect Cost
$226,989
Name
Sri International
Department
Type
DUNS #
009232752
City
Menlo Park
State
CA
Country
United States
Zip Code
94025