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Positive allosteric modulators at GABA(B) receptors exert intrinsic actions and enhance the influence of baclofen on light-induced phase shifts of hamster circadian activity rhythms.
MedLine Citation:
PMID:  21756929     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Light-induced phase shifts of hamster circadian activity rhythms are modulated by GABA(B) receptors. Recently, positive allosteric modulators (PAM)s at GABA(B) receptors were described, but it is not known whether they affect light-induced entrainment of circadian rhythms. Therefore, we studied the effects of two GABA(B) PAMs, GS39783 and RacBHFF, upon light-induced phase advances and delays of hamster circadian wheel-running activity rhythms. Wheel running activity was recorded for Syrian hamsters maintained in constant darkness. Drugs administered intraperitoneally were evaluated for their ability to modulate a light-induced shift of the circadian activity rhythm. Baclofen (3.75-15mg/kg) dose-dependently inhibited both light-induced phase advances and delays of hamster wheel running rhythms, and its actions were blocked by the selective GABA(B) antagonist, SCH50911 (5mg/kg). Neither GS39783 (3-30mg/kg) nor RacBHFF (0.63-10mg/kg) affected phase advances when injected alone, but both GS39783 (3mg/kg) and RacBHFF (10mg/kg) augmented the inhibitory effect of baclofen (5mg/kg). At doses above 3mg/kg, GS39783 and RacBHFF significantly inhibited phase delays alone, consistent with the notion of "agonist-allosteric" properties. GS39783 (0.5mg/kg), but not RacBHFF (10mg/kg), augmented the inhibitory action of baclofen on phase delays. These data are consistent with the possibility that GS39783 and RacBHFF act as PAMs at GABA(B) receptors inhibiting light-induced phase advances, yet that they also posses "allosteric agonist" actions at the (presumably separate) population of GABA(B) receptors modulating light-induced phase delays. GABA(B) receptors clearly warrant further investigation as agents for modulation of circadian dysfunction associated with CNS disorders such as depression.
Authors:
Robert L Gannon; Mark J Millan
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-7-6
Journal Detail:
Title:  Pharmacology, biochemistry, and behavior     Volume:  -     ISSN:  1873-5177     ISO Abbreviation:  -     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-7-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0367050     Medline TA:  Pharmacol Biochem Behav     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
Affiliation:
Department of Biology, Valdosta State University, Valdosta, Georgia USA.
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