The Problem of Paradoxical Sleep

The relationship between slow-wave sleep and paradoxical sleep is not a simple one. On the one hand there appears to be a functional link between the two. Thus, after destruction of the raphe system, paradoxical sleep appears only when slow-wave sleep has reached a certain daily threshold ( 15 percent) (Fig. 5). Similarly, following the injection of p-chlorophcnylalanine, the rate of occurrence of paradoxical sleep is closely related to the hrain concentration of serotonin (44). These facts lead to the hypothesis that serotonergic mechanisms involved during slow-wave sleep act as priming mechanisms for the triggering of paradoxical sleep (46). It is probable that these mechanisms are located in the caudal part of thc raphe system, since destruction of the caudal raphe leads to a very severe suppression of paradoxical sleep (relative to slow wave sleep), whereas destruction of th rostral raphe has little effect on paradoxical sleep (which may appear in the absence of slow-wave sleep).

On the other hand it has been revealed that the structures directly responsible for paradoxical sleep are located outside the structures (raphe nuclei) responsible for slow-wave sleep. By suppressing paradoxical sleep through limited lesioning of the dorso ateral pontine tegmentum (a procedure that does not interfere with slow-wave sleep), it was demonstrated that certain pontine structures different from the raphe system are essential to paradoxical sleep (50, 51).

Because monoamine oxidase inhibitors were shown to have the strongest selective suppressing effect upon paradoxical sleep, we undertook the re evaluation of previous results in the light of new findings obtained by histochemical techniques. The nuclei of the locus coeruleus, which were shown to be composed almost exclusively of monoamine oxidase-containing and noradrenalin-containing cells (37,52), were the target (Fig. 4). When a monoamine oxidase inhibitor (nialamide) is administered in the rat or the cat, the resulting selective suppression of paradoxical sleep is found to be correlated with the disappearance of monoamine oxidase staining in the locus coeruleus (29, 53). Moreover, the bilateral destruction of these nuclei produces a total selective suppression of paradoxical sleep (54, 55), whereas control lesions placed rostrally, medially, laterally, or caudally do not affect paradoxical sleep (Table 2). Only lesions immediately ventral to the locus coeruleus nuclei at the level of the nucleus reticularis pontis caudalis which probably involves efferent path ways) suppresses paradoxical sleep (55).

The fact that noradrenalin-containing nerve cells are located in the locus coeruleus suggests that noradrenergic mechanisms may play a role in paradoxical sleep. Destruction of both nuclei decreases the noradrenalin concentration significantly and selectively in rostral parts of the brain (55) (Table 2). In addition, numerous drugs which act upon noradrenalin synthesis may selectively suppress paradoxical sleep (56). This has been shown (57) with alpha-methyl p-tyrosine, which inhibits the synthesis of brain catecholamines at the level of tyrosine hydroxylase (58), and with di sulfiram (59), which impairs the synthesis of noradrenalin at the level of dopamine-beta-hydroxylase (60). On the other hand, alpha-methyl-m-tyrosine and alpha-methyldihydroxyphenylalanine, which may act as false transmitters (61), also have strong suppressive effects on paradoxical sleep in the cat (29, 62). Another indirect evidence of the intervention of a noradrenergic mechanism is the finding that there is an increased turnover of cerebral noradrenalin dur ing the rebound of paradoxical sleep which follows its selective deprivation in the rat (63).

In addition to noradrenalin, cholinergic mechanisms have been implicated in paradoxical sleep by certain pharmacological evidence. Atropine ( 1 to 2 milligrams per kilogram) suppresses paradoxical sleep in the cat (50, 64, 65), whereas eserine may facilitate it in pontile cats (50, 64). Direct injection of acetylcholine or carbachol in the vicinity of the nucleus of the locus coeruleus triggers paradoxical sleep in normal cats (66) . As indicated at the level of the peripheral nervous system (67), it is thus possible that acetylcholine may act as a triggering mechanism for noradrenergic mechanisms.

In sum, neuropharmacological, neurophysiological, and histochemical data provide a partial understanding of the succession of events involved in paradoxical sleep. Priming mechanisms lo ated in the caudal part of the raphe system act upon a target in the dorsolateral pontine tegmentum where densely packed monoamine oxidase containing and noradrenalin-containing neurons are located and where paradoxical sleep is triggered. The occur rence of paradoxical sleep may be inhibited by at least three categories of drugs (Fig. 7). This fact suggests that the paradoxical-sleep mechanism requires three keys in order to operate (deaminated serotonin catabolite, acetylcholine, and noradrenalin). Such a "fail-safe" mechanism contributes to the effectiveness of the organism in that it prevents the intrusion into waking of the hallucinatory processes involved in dreaming.

* Student's t-test values for P obtained by comparison with group A; NS; not significant. Each P column refers to the column that immediately precedes it.

Table 2. comparison, for various groups of cats with brain lesions, of the amounts of slow wave sleep and paradoxical sleep, expressed as (i) a percentage of recording time (10 to 13 days); (ii) the percentage of the nucleus locus coeruleus destroyed surgically; and (iii) the amounts of serotonin and noradrenalin in the brain rostral to the lesion, expressed as percent ages of the amounts in the brains of normal control cats. The group divisions are as follows: (A) cats that had undergone sham operations, used as controls in Student's t-test, (s) cats with total or subtotal hilateral lesions of the nucleus locus coeruleus that resulted in total suppression of paradoxical sleep; (c) cats with lesions lateral to the nucleus locus coeruleus involving the nuclei parahrachialis medialis and lateralis; (D) cats with lesions caudal to the nucleus locus coeruleus involving the vestibular nuclei. The percentages are mean values for an entire group, plus standard deviation.

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