Excitation of the pedunculopontine tegmental NMDA receptors induces wakefulness and cortical activation in the rat

Microinjection of the excitatory amino acid, L-glutamate into the brainstem pedunculo pontine tegmentum (PPT) has been shown to induce wakefulness, ho wever, it has been unclear that receptors mediate this effect. The aim of t his study was to test the hypothesis that in the PPT, L-glutamate induces c ortical activation and wakefulness via activation of NMDA receptors. To tes t this hypothesis, three sets of micro-injections into the PPT were carried out on two different groups of rats that were then allowed to move freely although chronic instrumentation recorded sleep/wake states. Three days aft er the initial control injections of saline, in a contra-lateral site, Grou p I was micro-injected with saline + glutamate (saline first, and glutamate 15 min later); after another 3 days, the same rats were micro-injected wit h the NMDA-receptor-specific antagonist, 2-amino-5-phosphonopentanoic acid, (AP5) + glutamate. Group II received the same initial control injections ( saline only), then AP5 + glutamate and the saline + glutamate micro-injecti ons last. In rats that were not pretreated with AP5, microinjection of a 90 ng dose of L-glutamate (0.48 nmol in a volume of 0.1 mul vehicle) kept ani mals awake for 2-3 hr by eliminating both slow-wave sleep (SWS) and rapid e ye movement (REM) sleep. These behavioral state changes were accompanied by concomitant increase in the power of gamma (gamma) frequency (20-60 Hz) wa ves in the cortical EEG. Pretreatment Of L-glutamate injection sites with 0 .48 nmol of AP5 blocked L-glutamate-induced-wakefulness and preserved a nor mal amount of wakefulness and sleep. Pretreatment with AP5 decreased the po wer of gamma -wave activity below its control level. These results support the hypothesis that the glutamate-induced-wakefulness and cortical activati on effects are mediated via the NMDA receptors. (C) 2001 Wiley-Liss, Inc.