30722 Sleep 5.qxd

RAPID EYE MOVEMENT (REM) SLEEP IS A SPECIAL BEHAVIORAL STATE identified by the polygraphic signs of activated cortical electroencephalogram (EEG), inactivity of the antigravity muscles, REMs, theta-frequency waves in the hippocampal EEG, and spiky waves in the pontine EEG (P-wave). Evidence from both rat and cat studies over the last 2 decades suggests that each of the events of REM sleep is executed by distinct cell groups in the brain stem.1-3 Each of these REM sleep sign-generating neurons is triggered and modulated by the activation of a special group of cells in the cholinergic cell compartment of the pedunculopontine tegmentum (PPT).2,4 In support of this statement, anatomic studies have shown that each of these individual REM sleepgenerating nuclei receives anatomic inputs from the PPT.5-12 In a number of studies, it has been shown that the cholinergic activation of individual REM sleep sign-generating nuclei expresses those REM sleep signs state independently.13-15 Single-cell recording studies in the rat and cat have shown that the majority of those PPT cells are more active during REM sleep than during slow-wave sleep (SWS).16-19 Spontaneous release of acetylcholine in the pontine reticular formation is greater during REM sleep than during waking and SWS.20,21 We have recently provided new data that indicate that the activation of cells within the PPT cholinergic cell compartment induces REM sleep.22-25 Electrical stimulation of the PPT causes increased acetylcholine release in the pontine reticular formation, indicating that cells within the PPT cholinergic cell compartment are one of the sources of acetylcholine in the pontine reticular formation during REM sleep.26 Neurotransmitter-mediated excitation and inhibition of brainstem cells are important processes for the regulation of REM sleep.2 In recent years, considerable progress has been made in identifying the neurotransmitters and receptors involved in the excitation of PPT cells that induce REM sleep, wakefulness, or both.22-25,27 However, the identification of neurotransmitters involved in the inhibition of PPT cells and suppression of REM sleep in freely moving animals remains incomplete. Based on single-cell activity patterns in the dorsal raphe (DRN) and locus coeruleus (LC) nuclei28-33 and a number of in vivo34-39 and in vitro pharmacologic studies,40-42 it has been proposed that serotonin and norepinephrine (NE) may inhibit PPT cell activity and in turn block REM sleep. This interpretation receives support from neuroanatomic studies that showed that the PPT receives afferent inputs from the DRN and LC.5,43-46 A microdialysis study in the freely moving cat has shown that the level of extracellular serotonin in the PPT is lowest during REM sleep and highest during wakefulness.47 The results of this microdialysis study suggest that increased serotonin levels in the PPT suppress REM sleep. In recent years, the rat has become one of the most popular animals used to study the mechanisms of sleep. However, until now, no other published study has targeted the effects of local application of serotonin, NE, or both serotonin and NE into the cholinergic cell compartment of the PPT in the freely moving rat. It is useful to see the effects of local application of serotonin and NE into the PPT cholinergic cell compartment in freely moving rats, especially since it has been found that activation of kainate receptors in the PPT cholinergic cell compartment induces REM sleep.24,25 In addition to NE and serotonin, it has been sug-