Biomedical subjects
Publications and source records attributed to W P Koella.
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.
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.
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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)
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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.
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.
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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.
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.