Catecholamines and the sleep-wake cycle II. REM sleep

Abstract

The exact role of catecholamines (CA) on REM sleep is still controversial. Lesion studies suggest that norepinephrine plays a neuromodulatory role in REM sleep. Support for this view is provided by pharmacological studies in which noradrenergic neurons are activated or inhibited. Thus, disturbances in the dynamic balance between neurochemical systems may alter the conditions under which optimal REM sleep takes place. Discrete radiofrequency lesions to the pontine giganto-cellular tegmental field (which includes the nuclei reticularis pontis oralis and caudalis and where cholinergic and cholinoceptive neurons have been described), result in the elimination of REM sleep. Circumscribed, electrolytic lesions of the locus coeruleus (IC) area, which only minimally extend beyond it, eliminate atonia and reduce PGO activity in REM sleep. Selective destruction of the LC or ascending noradrenergic axons with 6-hydroxydopamine does not result in significant changes of tonic or phasic components of desynchronized sleep. These results indicate that noradrenergic neurons are not necessary for the initiation and maintenance of REM sleep. Most probably, many of the effects attributed to noradrenergic structures are due to destruction of non-noradrenergic neurons and fibers of passage in the lesioned area. Inhibition of CA synthesis with α-methyl-p-tyrosine has resulted in conflicting effects on REM sleep, which could be related to factors other than NE depletion. Systemic administration of dopamine-β-hydroxylase inhibitors (disulfiram, diethyldithiocarbamate, FLA-63, fusaric acid) produced consistent reductions of REM sleep. However, the simultaneous increase of 5-HT and DA levels complicates the interpretation of these results. Selective pharmacological stimulation of presynaptic α-adrenergic (α2) receptors with clonidine, xylazine or α-methyl-dopa decreases REM sleep. Specific blockade of α 2-receptors with yohimbine, piperoxane or tolazoline also reduces desynchronized sleep, but increases wakefulness. In contrast, drugs with similar affinity for pre and postsynaptic (α1) adrenoceptors (phentolamine) markedly increase REM sleep. Compounds Compounds with agonistic activity at postsynaptic α-adrenergic sites (methoxamine) consistently reduce REM sleep, while derivatives with inhibitory activity restricted to these receptors (thymoxamine, prazosin) produce REM sleep increments. Results from studies where propranolol and isoproterenol were administered to laboratory animals point to an involvement of β-adrenergic mechanisms in REM sleep modulation. Although there is no direct evidence to support a dopaminergic influence upon REM sleep executive mechanisms, indirect pharmacological data suggests a neuromodulatory role for dopaminergic neurons. Direct dopaminergic agonists and antagonists show biphasic effects on REM sleep. Low dosages of apomorphine increase, while large doses decrease, REM sleep. Opposite effects are observed after the dopaminergic antagonist pimozide. These dose-dependent effects seem to be related to the activation or blockade of different receptors.