Abnormal response to stress and impaired NPS-induced hyperlocomotion, anxiolytic effect and corticosterone increase in mice lacking NPSR1

Zhu, Hongyan; Mingler, Melissa K.; McBride, Melissa L.; Murphy, Andrew J.; Valenzuela, David M.; Yancopoulos, George D.; Williams, Michael T.; Vorhees, Charles V.; Rothenberg, Marc E.

doi:10.1016/j.psyneuen.2010.01.012

« Previous Next »Psychoneuroendocrinology
Volume 35, Issue 8 , Pages 1119-1132, September 2010

Abnormal response to stress and impaired NPS-induced hyperlocomotion, anxiolytic effect and corticosterone increase in mice lacking NPSR1

Hongyan Zhu
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
- Graduate Program of Molecular and Developmental Biology, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Melissa K. Mingler
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
Melissa L. McBride
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
Andrew J. Murphy
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA
David M. Valenzuela
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA
George D. Yancopoulos
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA
Michael T. Williams
- Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
Charles V. Vorhees
- Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
- Corresponding author. Tel.: +1 513 636 8622; fax: +1 513 636 3912.
Marc E. Rothenberg
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
- Corresponding author. Tel.: +1 513 636 7210; fax: +1 513 636 3310.

Received 23 July 2009; received in revised form 15 January 2010; accepted 19 January 2010.

Summary

NPSR1 is a G protein coupled receptor expressed in multiple brain regions involved in modulation of stress. Central administration of NPS, the putative endogenous ligand of NPSR1, can induce hyperlocomotion, anxiolytic effects and activation of the HPA axis. The role of NPSR1 in the brain remains unsettled. Here we used NPSR1 gene-targeted mice to define the functional role of NPSR1 under basal conditions on locomotion, anxiety- and/or depression-like behavior, corticosterone levels, acoustic startle with prepulse inhibition, learning and memory, and under NPS-induced locomotor activation, anxiolysis, and corticosterone release. Male, but not female, NPSR1-deficient mice exhibited enhanced depression-like behavior in a forced swim test, reduced acoustic startle response, and minor changes in the Morris water maze. Neither male nor female NPSR1-deficient mice showed alterations of baseline locomotion, anxiety-like behavior, or corticosterone release after exposure to a forced swim test or methamphetamine challenge in an open-field. After intracerebroventricular (ICV) administration of NPS, NPSR1-deficient mice failed to show normal NPS-induced increases in locomotion, anxiolysis, or corticosterone release compared with WT NPS-treated mice. These findings demonstrate that NPSR1 is essential in mediating NPS effects on behavior.

Keywords: Neuropeptide S, Neuropeptide S receptor, NPSR1, Stress, Anxiety, Depression, Locomotor activity, Corticosterone