A novel role of pedunculopontine tegmental kainate receptors: a mechanism of rapid eye movement sleep generation in the rat

Abstract

Considerable evidence suggests that pedunculopontine tegmental cholinergic cells are critically involved in normal regulation of rapid eye movement sleep. The major excitatory input to the cholinergic cell compartment of the pedunculopontine tegmentum arises from glutamatergic neurons in the pontine reticular formation. Immunohistochemical studies reveal that both ionotropic and metabotropic receptors are expressed in pedunculopontine tegmental cells. This study aimed to identify the role of endogenous glutamate and its specific receptors in the pedunculopontine tegmentum in the regulation of physiological rapid eye movement sleep. To identify this physiological rapid eye movement sleep-inducing glutamate receptor(s) in the pedunculopontine tegmental cholinergic cell compartment, specific receptors were blocked differentially by local microinjection of selective glutamate receptor antagonists into the pedunculopontine tegmental cholinergic cell compartment while quantifying the effects on rapid eye movement sleep in freely moving chronically instrumented rats. By comparing the alterations in the patterns of rapid eye movement sleep following injections of control vehicle and selective glutamate receptor antagonists, contributions made by each receptor subtype in rapid eye movement sleep were evaluated. The results demonstrate that when kainate receptors were blocked by local microinjection of a kainate receptor selective antagonist, spontaneous rapid eye movement sleep was completely absent for the first 2 h, and for the next 2 h the total percentage of rapid eye movement sleep was significantly less compared to the control values. In contrast, when N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, groups I, II, and III metabotropic receptors were blocked, total percentages of rapid eye movement sleep did not change compared to the control values. These findings suggest, for the first time, that the activation of kainate receptors within the cholinergic cell compartment of the pedunculopontine tegmentum is a critical step for the regulation of normal rapid eye movement sleep in the freely moving rat. The results also suggest that the different types of glutamate receptors within a small part of the brainstem may be involved in different types of physiological functions.