We have identified a novel neuropeptide, termed NPS, that is predominantly expressed in a cluster of previously unidentified neurons in close vicinity to the noradrenergic locus coeruleus. The locus coeruleus is a brainstem structure involved in regulating sleep-wake cycles, arousal, attention and stress. Dysfunction of this brain area has been implicated in a number of disorders such as insomnia, narcolepsy and attention deficit hyperactivity disorder. More widespread expression of the NPS receptor is found in several brain areas, including cortex, thalamus and hypothalamus. Our preliminary results show that NPS promotes arousal when injected in mice. NPS also induces wakefulness while suppressing REM sleep and deep sleep in rats. Furthermore, NPS appears to produce anxiolytic-like effects. Therefore, NPS could represent a new transmitter system involved in neuronal modulation of vigilance and stress. We propose to study in detail the anatomical distribution of this novel transmitter system and the pharmacology of its receptor. We will determine the coexistence of NPS with known transmitters and its effect on the release of other transmitters involved in arousal. Furthermore, we will investigate its role in sleep and wakefulness and a possible involvement in attention and anxiety. Since no antagonist to the NPS receptor is currently available, we propose a genetic approach to delete the NPS gene in mice and study the behavioral consequences of NPS deficiency. Together, these studies will lay the foundation for understanding the physiological functions of NPS which may also yield new insights into human psychiatric disorders. A mutation in the human NPS receptor was recently found to be associated with increased risk of asthma. We will study the pharmacology of the mutant receptor isoforms which may help to understand the physiological consequences of the mutation in human airway tissue.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH071313-04
Application #
7409131
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Winsky, Lois M
Project Start
2005-04-08
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$279,290
Indirect Cost
Name
University of California Irvine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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Okamura, Naoe; Reinscheid, Rainer K; Ohgake, Shintaro et al. (2010) Neuropeptide S attenuates neuropathological, neurochemical and behavioral changes induced by the NMDA receptor antagonist MK-801. Neuropharmacology 58:166-72
Camarda, Valeria; Rizzi, Anna; Ruzza, Chiara et al. (2009) In vitro and in vivo pharmacological characterization of the neuropeptide s receptor antagonist [D-Cys(tBu)5]neuropeptide S. J Pharmacol Exp Ther 328:549-55
Guerrini, Remo; Camarda, Valeria; Trapella, Claudio et al. (2009) Further studies at neuropeptide s position 5: discovery of novel neuropeptide S receptor antagonists. J Med Chem 52:4068-71

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