The metabotropic glutamate (mGLU)2/3 receptor antagonist LY341495 [2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid] stimulates waking and fast electroencephalogram power and blocks the effects of the mGLU2/3 receptor agonist ly379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate] in rats.
The highly selective metabotropic glutamate (mGlu)2/3 receptor agonist LY379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate] completely suppresses rapid eye movement (REM) sleep and strongly depresses theta (6-10 Hz) and high-frequency (10-60 Hz) power in the waking and nonrapid eye movement (NREM) EEG, effects consistent with depressed brain excitation (arousal). We hypothesized the selective mGlu2/3 receptor antagonist LY341495 [2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid] given alone would 1) increase arousal, producing sleep-wake EEG effects opposite those of LY379268, and 2) block/reverse the effects of LY379268 when the drugs are coadministered. Rats with implanted electrodes were injected with 1, 5, or 10 mg/kg LY341495 at hour 5.5 of the dark period. In the coadministration study the rats received the same dose of LY341495 followed 30 min later by 1 mg/kg LY379268. LY341495 alone increased waking by reducing NREM and REM sleep. LY341495 also depressed low-frequency and stimulated high-frequency EEG power. It produced a sharp spike in theta power in waking but not NREM sleep, a striking state-dependent difference in pharmacological response. These changes indicate that blocking mGlu2/3 receptors increases brain arousal. Moreover, they show that mGlu2/3 receptors actively support arousal even in the absence of heightened glutamate excitation. The coadministration experiment demonstrates that LY341495 is selective in vivo since it dose-dependently attenuates or reverses the sleep-wake EEG effects of the highly selective mGlu2/3 receptor agonist LY379268. The capacity of mGlu2/3 receptor agonists and antagonists to alter the sleep wake balance suggests they could be developed to enhance sleep or sustain arousal. Their opposing actions on theta EEG could test the putative role of these oscillations in memory consolidation.
Feinberg
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University of California-Davis Sleep Lab, TB148, University of California-Davis, Davis, CA 95616, USA. ifeinberg@ucdavis.edu
Schoepp
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Hsieh
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KC
Darchia
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N
Campbell
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D000596:Amino Acids / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000818:Animals; D001143:Arousal / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000037:antagonists & inhibitors*; D003624:Darkness; D004569:Electroencephalography / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012890:Sleep / Q000187:drug effects; D012894:Sleep Stages / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects*; D014966:Xanthenes / Q000494:pharmacology*
D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; C118218:LY 379268; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C104723:glutamate receptor ionotropic, AMPA 3; C104722:glutamate receptor ionotropic, AMPA 2