A possible monoaminergic theory of sleep

Sleep cannot be explained any more by the passive relaxation of the wakeful ness system since transection (30) or limited lesions of the brain stem lead to a very marked increase in arousal. Thus there is little doubt that the problem of sleep is limited to the knowledge of the neural structures and mechanisms that periodically damp down the reticular activating system. This problem is, however, complicated by the fact that two different states of sleep (SWS and PS) are involved successively.

There is little doubt that the neural structures responsible for behavioral sleep are mainly, if not exclusively, located in the lower brain stem, and it appears al most certain that rostral structures (mostly-telencephalic) are necessary for the occurrence of synchronization (but not necessarily sleep) at the cortical and subcortical levels.

The search for sleep-inducing structures is thus limited to the brain stem. Whether these structures belong to some specific nuclei in the medulla or pons or to a discrete group of monoaminergic (serotonergic) neurons located mostly in the raphe system probably shall be solved in the near future.

The essential role played by the pontine tegmentum for the triggering of most tonic and phasic phenomena of PS is also supported by numerous experimental data, and it is very unlikely that any structures situated rostrally to the pons should play a determinant role in the induction of PS since the essential components of PS still appear periodically in chronic pontine cats. It should be emphasized that a group of noradrenergic neurons is apparently located in the dorsal part of the mediolateral pontine reticular formation, which plays a determinant role in the kiggering of PS. Thus both serotonergic neurons of the raphe complex and the catecholaminergic neurons of the pontine tegmentum appear to have a strategic and determinant position in the triggering of both states of sleep. Their intervention in sleep mechanisms is strongly supported by neuropharmacological data in brief, any alteration in brain monoamines leads to specific and obvious alteration of sleep, any increase in brain serotonin leads to an increase in SWS (and a parallel decrease in PS), and blockage of mono-amino-oxidase leads to elective suppression of PS whereas the release of monoamines at the monoaminergic terminals induced by reserpine leads to the elective occurrence of the specific PGO activity of PS.

There are many histochemical (114) and biochemical (193, 194) data that support the existence of an ascending serotonergic system with cells located mainly in the raphe system. The intervention of such an ascending system in the mecha nism of SWS appears likely since its almost total destruction led to a state of almost permanent wakefulness, whereas any attempt to increase the 5-HT content of the serotonergic neurons (which is revealed by the increase of the yellow fluorescence after injection of Nialamide) (114) led to an increase in SWS.

The process by which serotonergic neurons could act on the arousal system during SWS is still unknown and more facts about the amounts of bound and free 5-HT in the brain are required.

If the process governing SWS appears to be related to the entry of 5-HT in serotonergic cell bodies, the process of PS appears to be related to the release of monoamines at the monoaminergic terminals, since reserpine can trigger electively the most specific electrical phasic activity of PS; the existence of catecholaminergic mechanisms is strongly suggested by the histochemical structures of the dorsal part of the mediolateral pontine tegmentum (noradrenergic neurons) [group A6 of Dahlstrom and Fuxe (114)] and by the fact that the total atony of PS may appear if DOPA is injected after reserpine.

The physiological mechanism, which periodically acts (possibly at the mem brane level of monoaminergic terminals during PS) in a very subtle way almost similar to reserpine, is still a matter of speculation Thus, a very discrete sleep "lobby" composed of monoaminergic neurons, with cell bodies mostly located in the raphe system and the pontine tegmentum, appears to influence periodically during SWS and PS all other far more numerous "classical" neurons of the brain. For what purposes, during phylogeny, monoaminergic neurons were first responsible for sleep, and then for both sleep and dreaming, is a great challenge to neurophysiologists.

The author is much indebted to Prof Eric Neil, who undertook the difficult task of correcting the English version of this paper.