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

Abstract

Microinjection of the excitatory amino acid, L-glutamate into the brainstem pedunculo pontine tegmentum (PPT) has been shown to induce wakefulness, however, it has been unclear that receptors mediate this effect. The aim of this study was to test the hypothesis that in the PPT, L-glutamate induces cortical activation and wakefulness via activation of NMDA receptors. To test 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 after the initial control injections of saline, in a contra-lateral site, Group I was micro-injected with saline + glutamate (saline first, and glutamate 15 min later); after another 3 days, the same rats were micro-injected with 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-injections 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 microl vehicle) kept animals awake for 2-3 hr by eliminating both slow-wave sleep (SWS) and rapid eye movement (REM) sleep. These behavioral state changes were accompanied by concomitant increase in the power of gamma (gamma) frequency (20-60 Hz) waves in the cortical EEG. Pretreatment of L-glutamate injection sites with 0.48 nmol of AP5 blocked L-glutamate-induced-wakefulness and preserved a normal amount of wakefulness and sleep. Pretreatment with AP5 decreased the power of gamma-wave activity below its control level. These results support the hypothesis that the glutamate-induced-wakefulness and cortical activation effects are mediated via the NMDA receptors.