• Skip to primary navigation
  • Skip to main content
SRI InternationalSRI mobile logo

SRI International

SRI International - American Nonprofit Research Institute

  • About
    • Blog
    • Press room
  • Expertise
    • Advanced imaging systems
    • Artificial intelligence
    • Biomedical R&D services
    • Biomedical sciences
    • Computer vision
    • Cyber & formal methods
    • Education and learning
    • Innovation strategy and policy
    • National security
    • Ocean & space
    • Quantum
    • QED-C
    • Robotics, sensors & devices
    • Speech & natural language
    • Video test & measurement
  • Ventures
  • NSIC
  • Careers
  • Contact
  • 日本支社
Show Search
Hide Search
Biomedical sciences publications May 13, 2017 Article

Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics

SRI International May 13, 2017

Citation

Copy to clipboard


Black SW, Schwartz MD, Chen T-M, Hoener MC, Kilduff TS (2017). Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics. Biological Psychiatry 82 :623–633. doi:10.1016/j.biopsych.2016.10.012.

Abstract

Background: Narcolepsy, a disorder of rapid eye movement (REM) sleep, is characterized by excessive daytime sleepiness and cataplexy, a loss of muscle tone triggered by emotional stimulation. Current narcolepsy pharmacotherapeutics include controlled substances with abuse potential or drugs with undesirable side effects. As partial agonists at trace amine-associated receptor 1 (TAAR1) promote wakefulness in mice and rats, we evaluated whether TAAR1 agonism had beneficial effects in two mouse models of narcolepsy.

Methods: In the first experiment, male homozygous B6-Taar1 tm1(NLSLacZ)Blt (Taar1 knockout) and wild-type mice were surgically implanted to record electroencephalogram, electromyogram, locomotor activity, and body temperature, and the efficacy of the TAAR1 agonist, RO5256390, on sleep/wake and physiological parameters was determined. In the second experiment, the effects of the TAAR1 full agonist RO5256390 and partial agonist RO5263397 on sleep/wake, locomotor activity, body temperature, and cataplexy were assessed in two mouse narcolepsy models.

Results: RO5256390 profoundly reduced rapid eye movement sleep in wild-type mice; these effects were eliminated in Taar1 knockout mice. The TAAR1 partial agonist RO5263397 also promoted wakefulness and suppressed nonrapid eye movement sleep. Both compounds reduced body temperature in the two narcolepsy models at the highest doses tested. Both TAAR1 compounds also mitigated cataplexy, the pathognomonic symptom of this disorder, in the narcolepsy models. The therapeutic benefit was mediated through a reduction in number of cataplexy episodes and time spent in cataplexy.

Conclusions: These results suggest TAAR1 agonism as a new therapeutic pathway for treatment of this orphan disease. The common underlying mechanism may be the suppression of rapid eye movement sleep.

Share this

Facebooktwitterlinkedinmail

Biomedical sciences publications, Publication Article

How can we help?

Once you hit send…

We’ll match your inquiry to the person who can best help you.

Expect a response within 48 hours.

Career call to action image

Make your own mark.

Search jobs
Our work

Case studies

Publications

Timeline of innovation

Areas of expertise

Blog

Institute

Leadership

Press room

Media inquiries

Compliance

Privacy policy

Careers

Job listings

Contact

SRI Ventures

Our locations

Headquarters

333 Ravenswood Ave
Menlo Park, CA 94025 USA

+1 (650) 859-2000

Subscribe to our newsletter

日本支社

SRI International

  • Contact us
  • Privacy Policy
  • Cookies
  • DMCA
  • Copyright © 2022 SRI International