title: Comparative analysis of the neurophysiological profile of group II metabotropic glutamate receptor activators and diazepam: effects on hippocampal and cortical EEG patterns in rats.
abstract: Selective activation of the Group II metabotropic glutamate receptors 2/3 (mGlu2/3) by either full agonists or positive allosteric modulators (PAMs) show anxiolytic activity. In the present study the anxiolytic profile of mGlu2/3 receptor agonists LY-354740 and LY-404039 and the mGlu2 receptor PAM 1-methyl-2-((cis-3-methyl-4-(4-trifluoromethyl-2-methoxy)-phenyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyridine (MTFIP) were evaluated using neurophysiology-based assays. Activation of mGlu2/3 receptors by these compounds, as well as the positive control diazepam, significantly decreased the frequency of hippocampal theta oscillation elicited by stimulation of the brainstem nucleus pontis oralis (nPO), a characteristic action of anxiolytic compounds. Since the nPO is a critical region involved in regulation of rapid eye movement sleep, mGlu2/3 receptor activators were also tested on sleep parameters, as well as on cortical and hippocampal encephalography (EEG) activity. Both mGlu2/3 agonists and the mGlu2 PAM significantly prolonged REM sleep latency and reduced total REM sleep duration while during the active awake state all compounds lowered hippocampal peak theta frequency. However, diazepam and mGlu2/3 agonists/PAM elicited opposite changes in cortical EEG delta and beta bands. Delta power significantly increased after any of the mGlu2/3 compounds but decreased after diazepam. In the beta band, mGlu2/3 receptor agonists dose-dependently decreased beta power in contrast to the well-known beta activation by diazepam. These effects lasted 3-4h and could not be explained by modest, transient changes (<1h) in waking and slow wave sleep. The current observations support the role of mGlu2/3 receptor activators as potential anxiolytic compounds, but indicate a distinct action on cortical EEG activity which is different from the effects of GABA(A) PAMs. This article is part of a Special Issue entitled 'Anxiety and Depression'.
authors.affiliation: Department of Neuroscience, Pfizer Global Research and Development, Eastern Point Road, MS 8220-4366, Groton, CT 06340, USA. chester.j.siok@pfizer.com
authors.forename: Chester J
authors.initials: CJ
authors.lastname: Siok
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Cogan
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Shifflett
authors.forename: Angela C
authors.initials: AC
authors.lastname: Doran
authors.forename: Bernat
authors.initials: B
authors.lastname: Kocsis
authors.forename: Mihály
authors.initials: M
authors.lastname: Hajós
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D058256:Brain Waves / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects*; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005583:Fourier Analysis; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D009434:Neural Pathways / Q000502:physiology; D011149:Pons / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors; D012895:Sleep, REM / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects
chemical_list: D014151:Anti-Anxiety Agents; D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA; C104722:glutamate receptor ionotropic, AMPA 2; D003975:Diazepam