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-Taar1tm1(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.
Keywords
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Article info
Publication history
Published online: October 18, 2016
Accepted:
October 12,
2016
Received in revised form:
September 23,
2016
Received:
June 10,
2016
Identification
Copyright
© Society of Biological Psychiatry, 2016.
