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First published on September 21, 2004; DOI: 10.1124/jpet.104.076547

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Received for publication August 24, 2004.
Revised September 20, 2004.
Accepted for publication September 21, 2004.

The mGLU2/3 receptor antagonist LY341495 stimulates waking and fast EEG power and blocks the effects of the mGLU2/3 receptor agonist LY379268 in rats

Irwin Feinberg 1*, Darryle Darwin Schoepp 2, Kung-Chiao Hsieh 1, Nato Darchia 1, Ian Glenn Campbell 3

1 University of California, Davis 2 Eli Lilly and Company 3 UC Davis

* Address correspondence to: E-mail: ifeinberg{at}ucdavis.edu

Abstract

The highly selective mGlu2/3 receptor agonist LY379268 completely suppresses REM sleep and strongly depresses theta (6-10 Hz) and high frequency (10-60 Hz) power in the waking and NREM EEG, effects consistent with depressed brain excitation (arousal). We hypothesized the selective mGlu2/3 receptor antagonist LY341495 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 of 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.


Key words: EEG, REM, arousal, glutamate, metabotropic, sleep


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