title: Selective pharmacological blockade of the 5-HT7 receptor attenuates light and 8-OH-DPAT induced phase shifts of mouse circadian wheel running activity.
abstract: Recent reports have illustrated a reciprocal relationship between circadian rhythm disruption and mood disorders. The 5-HT7 receptor may provide a crucial link between the two sides of this equation since the receptor plays a critical role in sleep, depression, and circadian rhythm regulation. To further define the role of the 5-HT7 receptor as a potential pharmacotherapy to correct circadian rhythm disruptions, the current study utilized the selective 5-HT7 antagonist JNJ-18038683 (10 mg/kg) in three different circadian paradigms. While JNJ-18038683 was ineffective at phase shifting the onset of wheel running activity in mice when administered at different circadian time (CT) points across the circadian cycle, pretreatment with JNJ-18038683 blocked non-photic phase advance (CT6) induced by the 5-HT1A/7 receptor agonist 8-OH-DPAT (3 mg/kg). Since light induced phase shifts in mammals are partially mediated via the modulation of the serotonergic system, we determined if JNJ-18038683 altered phase shifts induced by a light pulse at times known to phase delay (CT15) or advance (CT22) wheel running activity in free running mice. Light exposure resulted in a robust shift in the onset of activity in vehicle treated animals at both times tested. Administration of JNJ-18038683 significantly attenuated the light induced phase delay and completely blocked the phase advance. The current study demonstrates that pharmacological blockade of the 5-HT7 receptor by JNJ-18038683 blunts both non-photic and photic phase shifts of circadian wheel running activity in mice. These findings highlight the importance of the 5-HT7 receptor in modulating circadian rhythms. Due to the opposite modulating effects of light resetting between diurnal and nocturnal species, pharmacotherapy targeting the 5-HT7 receptor in conjunction with bright light therapy may prove therapeutically beneficial by correcting the desynchronization of internal rhythms observed in depressed individuals.
authors: Neuroscience, Janssen Research and Development, LLC San Diego, CA, USA.
authors: Jonathan
authors: J
authors: Shelton
authors: Neuroscience, Janssen Research and Development, LLC San Diego, CA, USA.
authors: Sujin
authors: S
authors: Yun
authors: Department of Neurobiology, Center for Sleep and Circadian Biology, Northwestern University Evanston, IL, USA.
authors: Susan
authors: S
authors: Losee Olson
authors: Department of Neurobiology, Center for Sleep and Circadian Biology, Northwestern University Evanston, IL, USA.
authors: Fred
authors: F
authors: Turek
authors: Neuroscience, Janssen Research and Development, LLC San Diego, CA, USA.
authors: Pascal
authors: P
authors: Bonaventure
authors: Neuroscience, Janssen Research and Development, LLC San Diego, CA, USA.
authors: Curt
authors: C
authors: Dvorak
authors: Neuroscience, Janssen Research and Development, LLC San Diego, CA, USA.
authors: Timothy
authors: T
authors: Lovenberg
authors: Neuroscience, Janssen Research and Development, LLC San Diego, CA, USA.
authors: Christine
authors: C
authors: Dugovic
keywords: 5-HT7 receptor; circadian rhythms; depression; mood; non-photic; phase shift; photic; serotonin
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