A partial theory of sleep. A novel view of its phenomenology and organization.

The various stages of sleep are characterized by specific vigilance profiles across the universe of available behavioral systems. The induction and structuring of sleep and its adaptation to a variety of internal needs is the result of a general vigilance-controlling apparatus.

CNS-related (side-)effects of beta-blockers with special reference to mechanisms of action.

beta-Adrenoreceptor antagonists are liable to produce behavioural side-effects such as drowsiness, fatigue, lethargy, sleep disorders, nightmares, depressive moods, and hallucinations. These undesirable actions indicate that beta-blockers affect not only peripheral autonomic activity but also some central nervous mechanisms. In experimental animals beta-blockers have been found to reduce spontaneous motor activity, to counteract isolation-, lesion-, stimulation- and amphetamine-induced hyperactivity, and to produce slow-wave and paradoxical sleep disturbances. Furthermore, central effects such as tranquilizing influences are used for the treatment of conditions such as anxiety. Several different mechanisms of action could be responsible for these CNS effects: Centrally mediated specific actions on centrally located beta-adrenergic receptors, known to exist downstream from, and at the terminals of, 'vigilance-enhancing' central noradrenergic pathways. Centrally mediated specific actions on centrally located receptors of the non-adrenergic type; an affinity of some beta-blockers towards 5-HT-receptors is well documented. Centrally mediated non-specific actions on centrally located neurones, owing to the membrane-stabilizing effects of beta-blockers. Peripherally mediated actions whereby beta-blockers induce changes in the autonomic activity in the periphery, which are relayed to the CNS to induce changes in activity of a variety of central systems. It can be assumed that with any one of the beta-blockers all these mechanisms come into play, yet with varying degrees depending on characteristics of the drugs such as lipophilicity and hydrophilicity, the ratio of antagonist versus (partial) agonist properties, affinity to 'alien' receptor sites, strength of membrane-stabilizing activity, stereospecific affinity, and potency.

[Biochemistry and pharmacology of vigilance: role of neurotransmitters within the framework of vigilance control]. / Zur Biochemie und Pharmakologie der Vigilanz: Die Rolle der Neurotransmitter im Rahmen der Vigilanz-Kontrolle.

Biochemical, pharmacological and neurophysiological research has produced an ever increasing amount of evidence that a variety of (putative) neurotransmitter (NT) mechanisms is implicated in the gross regulation of the many waking behaviours as well as in the organization of sleep. Yet, few of these experimental findings have yielded information as to the exact--specific and detailed--role played by anyone of these "wet" transmission systems in this whole regulatory and organizational function. Based on a new "Universal Concept of Vigilance" we were led to conclude that the actions and influences of at least some of these humoral transmission instruments are considerably better understood, if they are interpreted as being the main controlling instruments of the many local vigilances--the individual levels of responsiveness in the many behavioral systems that are responsible for the making of the many behavioral components. In this new "model" the noradrenergic, cholinergic, dopaminergic, serotonergic, and, possibly, some traceaminergic ascending (and descending) pathways constitute the Output-Component of a larger, reflex-type Vigilance-Controlling Apparatus (VCA). The NA-, Ach-, and the DA-systems are assumed to upregulate (local) vigilance by enhancing reactivity in the neuronal networks that subserve the organization of said behavioral components. In particular, NA- and Ach-pathways can be assumed to enhance mainly (but not exclusively) vigilance in systems of higher functions, whereas DA-fibers probably handle upregulation of reactivity (i.e. eventually vigilance) in the various motor systems. The efficacy of these various aminergic transmission systems is assumed to be further enhanced by a variety of polypeptidergic agents (e.g. TRH, Vasopressin, 4-10-ACTH, enkephalin). In turn, serotonergic pathways are involved as vigilance-reducing instruments. To explain the production of the, for the various waking activities as well as for the various phases and stages of sleep, proper and characteristic vigilance-profiles one has to assume that the activity of these output-channels is per se controlled by a coordinating central apparatus--the very "center"--of VCA.(ABSTRACT TRUNCATED AT 400 WORDS)

Feedback control of noradrenaline release as a function of noradrenaline concentration in the synaptic cleft in cortical slices of the rat.

Cortical slices incubated with [3H]noradrenaline (NA) were used to study quantitatively the infelucne of the NA concentration in the synaptic cleft on electrically induced release of [3H]NA from adrenergic nerve terminals. Stimulation-induced [3H]-overflow was regarded to be proportional to the NA concentration in the synaptic cleft. High concentrations of piperoxan or clonidine were used to block, or maximally stimulate, respectively, the presynaptic alpha-receptors and thus to eliminate feedback control. These two extreme conditions were thought to delineate maximal feedback range. With alpha-receptors not artifically manipulated, [3H]overflow increased with stimulus intensity, yet not in proportion to the [3H]-overflow when the presynaptic alpha-receptors were blocked, demonstrating increasing feedback inhibition with increasing NA concentrations in the synaptic cleft. Feedback inhibition of NA release was shown to depend in an exponential fashion on NA concentration in the synaptic cleft. The slope of the regression line indicated that maximal inhibition of NA release occurred with NA concentrations in the synaptic cleft 65,000--700,000 times higher than threshold concentration. Data from experiments with different stimulus rates also supported the notion of feedback control of NA release.

Epileptic phenomena induced in the cat by the antidepressants maprotiline, imipramine, clomipramine, and amitriptyline.

The epileptogenic properties of four tricyclic antidepressant drugs: maprotiline, imipramine, clomipramine, amitriptyline, were investigated in locally anesthetized cats immobilized with gallamine and supplied with neocortical, hippocampal, and reticular recording electrodes. The drugs were infused intravenously at a constant rate (0.5 or, in some cases, 0.25 mg/kg per min) up to a final dose of 45 mg/kg. Already in small doses (1 to 5 mg/kg) all four antidepressants produced local signs of epileptiform pathology. Generalized sustained discharges occurred, on the average, at between 20 and 25 mg/kg with all four drugs. Imipramine and amitriptyline, after the first or first few generalized discharges, led to a pattern of repeated short generalized seizures alternating with silent periods. Maprotiline invariably produced this later alternating pattern only after a 10- to 30-min period of a seminormal high amplitude pattern. Clomipramine assumed a position between maprotiline on the one hand and imipramine and amitriptyline on the other. Starting at doses of 2-4 mg/kg, imipramine, clomipramine and amitriptyline, all three being norepinephrine and serotonin uptake inhibitors, induced a high amplitude "sleep" pattern. Maprotiline, a norepinephrine uptake inhibitor, which is thought devoid of serotonin-uptake inhibiting properties, led to high amplitude slow waves only with doses of at least 12.5 to 15 mg/kg.

Inhibition of nigral and neocortical cells by gamma-hydroxybutyrate: a microiontophoretic investigation.

gamma-Hydroxybutyrate (GHB) and gamma-aminobutyrate (GABA) were applied microiontophoretically near spontaneously active cells in the substantia nigra and the neocortex of chloral hydrate-anaesthetized rats. Whereas GABA in "low doses" (i.e. 20 nA ejection currents) depressed the activity of cells in both areas, GBH reduced the firing rate only when the compound was expelled with two to three times higher ejection currents. Under these conditions GHB depressed about half of the nigral but the majority of the neocortical cells tested. The depressant action of GABA was readily antagonized by microiontophoretic bicuculline methiodide whereas the effects of GHB were resistant to this alkaloid. Intraperitoneally administered GHB in doses of 300 and 600 mg/kg reduced the firing rate of the majority of spontaneously active neocortical cells. In conclusion, GHB inhibits the firing of nigral and neocortical neurons. However its effects are not mediated through the activation of bicuculline-sensitive GABA receptors.

The biological activity of d- and l-baclofen (Lioresal).

Racemic d,l-baclofen and l-baclofen depressed the patellar, flexor, linguo-mandibular (0.1--30 mg/kg i.v.) and the H-reflex (1--3 mg/kg i.v.) in a dose-dependent fashion. Racemic and l-baclofen partly antagonized electroshock-induced convulsions in mice (30--60 mg/kg p.o.) and depressed the firing rate of nigral cells when applied iontophoretically. d,l-Baclofen and l-baclofen (0.1--3.0 mg/kg i.v.) moderately reduced the blood pressure in cats. Dextrorotatory baclofen, at identical doses was inactive in all these tests. It is concluded that the biological activity of baclofen resides with the l-enantiomer.

Activation of an inhibitory noradrenergic pathway projecting from the locus coeruleus to the cingulate cortex of the rat.

Repetitive stimulation of the locus coeruleus evoked strong inhibition of the firing rate of about 50% of cells of the cingulate rat cortex. Forty per cent of the cells were not affected and 9% were excited by stimulation of the locus coeruleus. Pretreatment of the rats with reserpine and alpha-methyl-p-tyrosine drastically reduced the percentage of cells inhibited by locus coeruleus stimulation. The cells inhibited in response to stimulation of the locus coeruleus as well as those not inhibited were depressed by microiontophoretically applied norepinephrine. This inhibitory action of NE was observed in rats anesthetized either with urethane, chloral hydrate or with Nembutal. The transsynaptically elicited, as well as the norepinephrine elicited, depression of the cells' discharge rate was antagonized by the microiontophoretically applied beta-receptor blocking drug MJ 1999. These data suggest that the inhibitory action on cingulate cortical cells of locus coeruleus stimulation is mediated by the dorsal ascending noradrenergic pathway.

Influence of vincamine and piracetam on sleep--waking pattern of the cat.

The effect of Vincamine and Piracetam, two geriatric drugs, on sleep behavior of the laboratory cat was studied. The animals were chronically prepared for recording of the EEG of the cerebral cortex, the lateral geniculate body, and the hippocampus, and for recording of eye movements, the muscular tonus and respiration. During the experiment, sleep and waking behavior were monitored by the above mentioned telemetrically transmitted indicators and also through observation via closed-circuit television. Both Vincamine and Piracetam in doses of 1 and 300 mg/kg p.o., respectively, enhance absolute and relative amounts of paradoxical sleep (PS). Smaller doses have a lesser or no effect on PS. Larger doses again have little effect or else, in the first few hours after application, reduce PS and total amount of sleep. Both drugs have little effect on slow wave and total sleep. Piracetam, but not Vincamine, reduces the prominent frequency of the theta band in hippocampus during PS. The PS-enhancing effect of the two geriatric drugs may be related to their memory-improving influence.