Modulation of group II metabotropic glutamate receptor (mGlu2) elicits common changes in rat and mice sleep-wake architecture.
Compiling pharmacological evidence implicates metabotropic glutamate mGlu(2) receptors in the regulation of emotional states and suggests positive modulators as a novel therapeutic approach of Anxiety/Depression and Schizophrenia. Here, we investigated subcutaneous effects of the metabotropic glutamate mGlu(2/3) agonist (LY354740) on sleep-wake architecture in rat. To confirm the specific effects on rapid eye movement (REM) sleep were mediated via metabotropic glutamate mGlu(2) receptors, we characterized the sleep-wake cycles in metabotropic glutamate mGlu(2) receptor deficient mice (mGlu(2)R(-/-)) and their arousal response to LY354740. We furthermore examined effects on sleep behavior in rats of the positive allosteric modulator, biphenyl-indanone A (BINA) alone and in combination with LY354740 at sub-effective doses. LY354740 (1, 3 and 10 mg/kg) dose-dependently suppressed REM sleep and prolonged its onset latency. Metabotropic glutamate mGlu(2)R(-/-) and their wild type (WT) littermates exhibited similar spontaneous sleep-wake phenotype, while LY354740 (10 mg/kg) significantly affected REM sleep variables in WT but not in the mutant. In rats, BINA (1, 3, 10, 20, 40 mg/kg) dose-dependently suppressed REM sleep, lengthened its onset latency and slightly enhanced passive waking. Additionally, combined treatment elicited a synergistic action on REM sleep variables. Our findings show common changes of REM sleep variables following modulation of metabotropic glutamate mGlu(2) receptor and support an active role of this receptor in the regulation of REM sleep. The synergistic action of BINA on LY354740's effects on sleep pattern implies that positive modulators would tune the endogenous glutamate tone suggesting potential benefit in the treatment of psychiatric disorders, in which REM sleep overdrive is manifested.
Ahnaou
Abdellah
A
Dept. Neuroscience, A Division of Janssen Pharmaceutica NV, Johnson & Johnson Pharmaceutical Research and Development, RED Europe, Beerse, Belgium. aahnaou@prd.jnj.com
Dautzenberg
Frank M
FM
Geys
Helena
H
Imogai
Hassan
H
Gibelin
Antoine
A
Moechars
Dieder
D
Steckler
Thomas
T
Drinkenburg
Wilhelmus H I M
WH
D000494:Allosteric Regulation; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D004338:Drug Combinations; D018698:Glutamic Acid / Q000378:metabolism; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects*; D012895:Sleep, REM / Q000187:drug effects; D013379:Substrate Specificity; D014851:Wakefulness / Q000187:drug effects*
D001713:Biphenyl Compounds; D001643:Bridged Bicyclo Compounds; D004338:Drug Combinations; D007189:Indans; D018094:Receptors, Metabotropic Glutamate; C522461:biphenyl-indanone A; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D018698:Glutamic Acid; C104753:eglumetad