Showing papers in "Journal of Neural Transmission in 1973"

In-vivo measurements of tryptophan and tyrosine hydroxylase activities in mouse brain.

Abstract: A single intraperitoneal injection of NSD 1015 (3-hydroxybenzyl-hydrazine HCl, 100 to 200 mg/kg), an inhibitor of the aromatic amino acid decarboxylase, caused an initially linear accumulation of 5-hydroxy-tryptophan (5-HTP) and 3, 4-dihydroxyphenylalanine (DOPA) in mouse brain. The initial rate of accumulation of 5-HTP after NSD 1015 and that of 5-hydroxytryptamine (5-HT) after treatment with the monoamine oxidase inhibitor pargyline were almost identical (about 1.7 nmoles/g·h−1 corresponding to a turnover time of 1.6 h) and may represent the true rate of 5-HT synthesis. About 60 min after pargyline, when the 5-HT level was doubled, the rate of 5-HT synthesis was partially inhibited, probably due to feedback inhibition. The observations on DOPA accumulation after NSD 1015 were in essential agreement with earlier rat brain data and suggest that the rate constants of catecholamine synthesis are similar in the brains of the two species.

On the origin of homovanillic acid (HVA) in the cerebrospinal fluid.

Abstract: The contribution of homovanillic acid by the caudate nuclei to the cerebrospinal fluid has been assessed quantitatively on the basis of available clinical-neurochemical and animal-experimental data. A considerable fraction of the caudatal tissue may be involved in this function.

Sensitization by caffeine of central catecholamine receptors.

Abstract: Mice, pretreated with reserpine, 10 mg/kg, were given various doses of a mixture of ET 495+clonidine, agents known to stimulate dopamine and noradrenaline receptors respectively. Some animals received caffeine, 25 mg/kg, in addition. After the last injection, the motor activity was recorded. Caffeine did not reverse the reserpine-induced suppression of motility but produced a fourfold increase in the reversing effect of ET 495+clonidine. The same result was obtained when in addition the synthesis of catecholamines had been blocked at the tyrosine hydroxylase step. Other animals received caffeine or saline injections at various time intervals after reserpine. The recovery of motility occurred about 20 h earlier in animals treated with caffeine as compared with saline controls. Caffeine also partially counteracted the hypothermia caused by reserpine. Some animals were given the dopamine receptor-blocking agent, pimozide or caffeine or both. Pimozide inhibited both the spontaneous and the caffeine-induced motility. It is concluded that caffeine causes sensitization of central catecholamine receptors.

Further studies on the mechanism of antipsychotic action: potentiation by alpha-methyltyrosine of thioridazine effects in chronic schizophrenics.

Abstract: Six chronic schizophrenics with stationary symptomatology and treated since more than one year with thioridazine in a fixed dose schedule were examined by means of two different rating scales. The thioridazine dosage was then considerably reduced, leading to reappearance of schizophrenic symptoms. The tyrosine hydroxylase inhibitor, α-methyltyrosine (2 g daily) was then given as additional treatment, and the thioridazine dosage necessary to reattain the pre-trial level of symptomatology was titrated. This dosage, as well as the simultaneous thioridazine plasma levels, were found to be considerably reduced by α-methyltyrosine. The efficacy of this agent as an inhibitor of tyrosine hydroxylase was ascertained by demonstrating a marked reduction in cerebrospinal fluid homovanillic acid. The observations confirm our earlier data and lend additional support for the hypothesis that central catecholamine neurotransmission is involved in the antipsychotic action of neuroleptic agents.

Rapid accumulation of H3-serotonin in brains of rats receiving intraperitoneal H3-tryptophan: effects of 5,6-dihydroxytryptamine or female sex hormones.

Abstract: The specific activities of brain and plasma H3-tryptophan and brain H3-serotonin increased approximately linearly for only 6 min after animals received intraperitoneal tracer doses of H3-tryptophan. The maximum rate of brain serotonin synthesis could thus be estimated from data collected during this interval, but not thereafter. Pretreatment of rats with intraventricular 5, 6-dihydroxytryptamine, a compound that damages serotoninergic neurons, decreases brain tryptophan and serotonin concentrations, accelerates the labelling of brain tryptophan by injected H3-tryptophan, and markedly decreases the rate at which H3-tryptophan accumulates as brain H3-serotonin. The treatment of oophorectomized rats with estradiol and progesterone does not appear to modify brain serotonin synthesis.

Effects of chlorimipramine and protriptyline on the hyperactivity induced by 5-hydroxytryptophan after peripheral decarboxylase inhibition in mice.

Abstract: DL-5-HTP in doses from 100 mg/kg is reported to increase the spontaneous motor activity in mice pretreated with L-α-hydrazino-α-methyl-β-(3, 4-dihydroxyphenyl)-propionic acid (MK-486), an inhibitor of peripheral aromatic aminoacid decarboxylase. Exogenously administered 5-HTP gives rise to accumulation of 5-HT in both central 5-HT-and catecholamine-neurons. The stimulant effect of DL-5-HTP may be mediated via increased activation of 5-HT receptors or, via displacement, increased activation of catecholamine receptors. In the present experiment pre-treatment with chlorimipramine, 25 mg/kg concomitant with MK-486 markedly potentiated the stimulant effect of DL-5-HTP on motor activity,i.e. the dose response curve was shifted to the left. DL-5-HTP, 75 mg/kg, induced in these animals a pronounced increase of the motor activity but had no significant effect on the brain concentrations of DA or NA. Pre-treatment with protriptyline-HCl, 25 mg/kg, concomitant with MK-486 did not potentiate the stimulant effect of DL-5-HTP. The results indicate that the DL-5-HTP induced motor activity is largely dependent on an increased activation of central 5-HT receptors.

Dopamine receptor site sensitivity in hyperthyroid guinea pigs: A possible model of hyperthyroid chorea

Abstract: Guinea pigs made hyperthyroid were found to have increased responsiveness to dopaminergic stimulation of the striatum as measured by the dosage of apomorphine necessary to elicit stereotyped behavior. A dosage of apomorphine which produced stereotyped behavior in only 3 out of 36 euthyroid guinea pigs induced this behavior in 18 out of 20 hyperthyroid guinea pigs. This observation suggests that striatal dopamine receptor site sensitivity is increased in hyperthyroidism and is consistent with the hypothesis that increased receptor site sensitivity plays a role in the pathophysiology of hyperthyroid chorea.

Release of dopamine from central noradrenaline and dopamine nerves induced by a dopamine-β-hydroxylase inhibitor

Abstract: The effect of the dopamine-β-hydroxylase inhibitor bis-(4-methyl-1-homopiperazinylthiocarbonyl)-disulphide (FLA-63) on the release of dopamine and noradrenaline was studied in regions of the rat central nervous system rich in dopamine or noradrenaline nerve terminals. The release was investigated by analyzing the accumulation of the 3-0-methylated catecholamines after inhibition of the monoamine oxidase by nialamide. In the dopamine-rich corpus striatum, the concentration of dopamine was unchanged but its release was enhanced after treatment with FLA-63. The noradrenaline concentration and release were markedly reduced. In the areas containing mainly noradrenaline nerve terminals, dopamine accumulated but did not stoichiometrically replace the missing noradrenaline. There was a pronounced release of dopamine from the noradrenaline nerves after the dopamine-β-hydroxylase inhibiticn. This release may, at least partly, explain why noradrenaline is not stoichiometrically replaced by dopamine.

Early effects of monoamine oxidase inhibitors on dopamine metabolism and monoamine oxidase activity in the neostriatum of the rat

Abstract: Dopamine levels in the neostriatum of the rat were estimated at various times after pargyline (75 mg/kg), pheniprazine (4 mg/kg) and tranylcypromine (20 mg/kg) intraperitoneal injections. Depending on the inhibitor used, the amine levels reached 135 to 150% of control values within 10 min. During the 20 min which followed this rapid linear rise, DA levels increased in tissues at a much slower rate. As indicated by the estimation of MAO activity using14C-tyramine or kynuramine as substrates, the three drugs induced a complete inhibition of the enzyme activity within 5 min. A similar effect was seen after pheniprazine and tranylcypromine with14C-dopamine as substrate, but the maximal inhibition never exceeded 80% after pargyline treatment. As revealed by the “in vivo” 3 min initial accumulation of3H-H2O seen at the end of a local infusion of L. 3. 5-3H-tyrosine, the rate of the first step of DA synthesis was unchanged 5 min after pargyline treatment but significantly reduced 10 min after the drug injection. This explains the sudden interruption in the rise of DA levels observed shortly after the MAO inhibitors injection. DA synthesis rate was calculated from the initial (5 min) rate of DA accumulation and was found to be 148 to 190 nmole/g/hr depending on the inhibitor used.

Experimental modulation of hypothalamic content of the gonadotropic releasing factors by pineal factors in the rat.

Abstract: 1e) The pineal fraction F 3 increased the hypothalamic FSH-and LH-RF contentin vitro andin vivo. This may be a consequence of a decrease in the secretion of the hypothalamic releasing factors in presence of the F 3 pineal factor. 2e) Serotonin modifies the hypothalamic gonadotropic RF content inhibiting the secretion and synthesis of the releasing factors. 3e) As with serotonin, microinjections of melatonin into the lateral ventricle performed at the same time as subcutaneous injections of nialamide are followed by a significant decrease of hypothalamic RF content.

L-dopa level in plasma, primary condition for the kinetic effect

Abstract: Intravenous or oral application of L-Dopa increased not only the plasma level but led at the same time to an improvement of the kinetic behaviour. A combined intravenous or oral administration of L-Dopa and the decarboxylase inhibitor Ro 4-4602 stop the damage of this peripheral L-Dopa-metabolism for the most part and therefore a higher L-Dopa-plasma-level is reached and the increase lasts longer.

Clinical and EEC studies on the emaciation (anorexia nervosa) due to disturbed function of the brain stem

Abstract: Fundamentally anorexia nervosa is considered as a metabolic and endocrinologic disorder due to a possible disturbance of hypothalamic functions. Some profound emotional and personality disorders are also stressed in its etiology. Only a few studies of the electroencephalograms in anorexia nervosa have been published. The purpose of the present study is to show the significance of electroencephalograms in the etiology of emaciation, especially that which is due to anorexia nervosa.

Effect of chronically administered L-dopa on dopa 5HTP decarboxylase and tyrosine and tryptophan hydroxylases in cat brain.

Abstract: The activity of tyrosine and tryptophan hydroxylases and of Dopa/ 5-HTP decarboxylase was measured in different structures of the brain of cats administered L-Dopa (100 mg/kg/day,per os) during several consecutive days The activity of tyrosine hydroxylase which is unchanged after 4 and 7 days of treatment, respectively, is significantly decreased after 21 days of L-Dopa The activity of tryptophan hydroxylase is normal after 4 days of L-Dopa but it is significantly decreased after 7 and 21 days of L-Dopa, respectively The activity of decarboxylase is normal after 4 days of L-Dopa but it is significantly increased after 7 and 21 days of L-Dopa, respectively

Über die Wirkung bestimmter Aminosäuren auf das Ergebnis des Überwärmungstests bei Multiple-Sklerose-Kranken

Abstract: Bei Multiple-Sklerose-(MS-)Patienten finden sich durchwegs stark verminderte Werte der Flimmerverschmelzungsfrequenz (FVF). Selbst bei klinisch voll remittierten Kranken bleibt die FVF — offenbar als Folge des zum Teil subklinisch verlaufenden Entmarkungsprozessesim pathologisch erniedrigten Bereich. Bei Warmebelastungen kommt es — parallel zum Anstieg der Korpertemperatur — bei MS-Kranken zu einer Verschlechterung neurologischer Herdsymptome, zum Teil werden solche erst durch die Belastung manifest. Die FVF nimmt im Laufe der Belastung weiter ab. Diese fur die MS charakteristischen Vorgange sind passager und auf die Dauer der Erhohung der Korpertemperatur beschrankt. Durch die vorherige Zufuhr der als Precursoren von Adrenalin und Noradrenalin bzw. Serotonin bekannten Aminosauren Tyrosin bzw. Tryptophan gelingt es, das Absinken der FVF durch die Erwarmung vollkommen zu kupieren, wahrend andere Aminosauren, wie z. B. Glutaminsaure und Asparaginsaure, wirkungslos sind. Die Befunde sprechen fur Storungen in den Neuro-Transmitter-Systemen bei der MS, deren Beseitigung moglicherweise auch fur die Therapie der MS von Bedeutung sein konnte.

Further studies on the behavioural and biochemical interaction between caffeine and L-DOPA.

Abstract: Mice, pretreated with the inhibitor of peripheral DOPA decarboxylase MK 486, were given caffeine, 25 mg/kg, or L-DOPA, 125 mg/kg, or both. The locomotor activity of the animals recorded for 2 h, doubled after caffeine whereas the effect of L-DOPA varied from depression to a slight hyperactivity. In combination the two drugs produced a tenfold increase in locomotor activity. The accumulation of dopamine in the brain, and the levels of DOPA in both brain and plasma following administration of L-DOPA, all increased when caffeine was given beforehand. However, caffeine did not modify the effects of L-DOPA on brain noradrenaline, 3-methoxytyrosine, 5-hydroxytryptamine, and 5-hydroxyindolacetic acid significantly. In some experiments3H-tyrosine was given before MK 486, caffeine and/or L-DOPA in order to label the central catecholamine stores. The disappearance of brain3H-NA and3H-DA following L-DOPA was not significantly changed by caffeine. From these and earlier data it is suggested that part of the potentiating effect of caffeine on the L-DOPA induced motility is due to the increased cerebral level of dopamine and part to a catecholamine-receptor sensitizing effect of caffeine.

The inhibitory effect of 5-methoxytryptophol on ovarian weight, follicular growth and egg production of adult white leghorn hens (Gallus domesticus L.).

Abstract: Identical age, body weight, or initial comb size are not useful as parameters in analysing effects of pineal substances on the gonadal system of adult white leghorn hens. A combination, however, of the initial comb size with the frequency of oviposition proved to be an adequate parameter.

The stimulatory effects of several concentrations of 5-methoxytryptophol on testicular growth in the white leghorn (Gallus domesticus L.).

Abstract: Concerning the gonads, the initial comb size in white leghorn cockerels proved to be a parameter which permits a more exact comparison of control and experimental animals, than the generally used parameters of identical age and/or body weight. As in literature contradictory results are described after injecting different concentrations of 5-methoxyindoles, it may be possible that these results can be explained by the parameters used. To analyse this, several concentrations of 5-methoxytryptophol were injected in increasing amounts in white leghorn cockerels, using the comb size as a parameter. In all experiments a stimulatory effect of 5-methoxytryptophol on testicular weight was observed. Administration of the smallest concentrations (0.1–3.5μg, exp. I, and 1.0–35μg, exp. II) showed an acceleration of the growing rhythm of the testes if compared with the control animals. With the comb size as a parameter it was possible to analyse the degree of stimulation in comb size units. Administration of 2.5–87.5μg (exp. III) and of 10–350μg (exp. IV) of 5-methoxytryptophol resulted also in a stimulatory activity on testicular growth; acceleration of the growing rhythm, however, now proved to be irregular and could not be compared with the growing pattern of the testes in the control animals.

Missing indicator function of growth hormone and luteinizing hormone blood levels for dopamine and serotonin concentration in the human brain.

Abstract: To evaluate if the peripheral concentration of human growth hormone (GH) and luteinizing hormone (LH) in the blood could serve as an indicator for the brain concentration of dopamine and serotonin, as it could be anticipated from animal experiments, the effect of intravenous administration of L-DOPA and DL-5-HTP upon GH and LH blood levels in normal male volunteers was investigated.

Antagonism by DL-threo-DOPS of the suppression of a conditioned avoidance response induced by a dopamine-beta-hydroxylase inhibitor.

Abstract: The administration of a dopamine-β-hydroxylase inhibitor, FLA-63 [bis (4-methyl-l-homopiperazinylthiocarbonyl) disulfide], 200 mg/kgp o induced a partial disruption of a conditioned avoidance response (CAR) in mice The CAR was suppressed to 75 per cent of controls 2 h, but not 4, 8, or 24 h, after the FLA-63 treatment The same dose of FLA-63 reduced brain noradrenaline to about 35 per cent of controls 2 h after the administration and to about 30 per cent of controls at the 8 h interval There was a slight increase in brain dopamine 4 and 8 h after the FLA-63 administration

Inhibition of brain protein synthesis by doses of L-DOPA that disaggregate brain polyribosomes.

Abstract: Rats receiving doses of L-DOPA sufficient to cause disaggregation of brain polyribosome profiles exhibitin vivo inhibition of uptake of14C-leucine or14C-lysine into brain protein coincident with the disaggregation.

Release of dopamine from central noradrenaline nerves after treatment with reserpine plus amphetamine.

Abstract: The dexamphetamine-induced release of dopamine and noradrenaline was studied in regions of the rat central nervous system rich in dopamine or noradrenaline nerve terminals by analyzing the accumulation of the 3-O-methylated catecholamines after inhibition of the monoamine oxidase. Reserpine pretreatment almost completely inhibited the amphetamine-induced release of noradrenaline from the noradrenaline nerves and reduced the dopamine release from the dopamine nerves by about one third. Amphetamine caused a release of dopamine, instead of noradrenaline, from the noradrenaline nerves after pretreatment with reserpine, and this replacement accounted for about two thirds of the missing noradrenaline. This dopamine was found to be of small functional significance due to a weak stimulating action on the noradrenaline receptors of the effector cells.

Ultrastructural evidence against in vivo disaggregation of brain polyribosomes after administration of L-dopa or phenylalanine.

Abstract: L-dopa or phenylalanine was injected intraperitoneally into immature rats. Brain samples fixed and embedded by conventional methods were sectioned for electron microscopic study. In contrast to chemical evidence in the literature for disaggregation of brain polysomes in fractions of whole brain from animals so treated, we found no ultrastructural evidence of disaggregation in either neurons or glial cells. The fact that we and others have observed polysome disaggregation in electron micrographs of sections from other types of animal experiments suggests that our observation of stable polysomes in the present work is not the result of technical artifact, and that the disaggregation observed in brain fractions by others had probably not occurred in their intact animals. It is unlikely that the behavioral and physiological changes occurring in patients treated with L-dopa can be correlated with the state of aggregation of brain polyribosomes.

Plasma growth hormone and insulin response to levodopa and amantadine.

Abstract: Blood levels of growth hormone, insulin and glucose were studied in 63 patients before and after intravenous levodopa (1.5 mg/kg), oral levodopa (0.5 g and 1.0 g) and amantadine (100 mg). A significant increase of growth hormone concentrations was found after intravenous and oral 1.0 g doses. No significant differences were found in insulin and glucose concentrations.

Exploratory activity and conditioned avoidance acquisition after early postnatal 6-Hydroxydopamine administration

Abstract: Newborn rats were treated with 3 injections of 6-hydroxydopamine (6-OHDA) either subcutaneously (s. c.) or intracerebrally (i. cer.).General motor activity, exploratory activities (crossing and rearing) and acquisition of conditioned avoidance response (CAR) in shuttle-box were tested in the course of the 9th postnatal week. 50μg/g s. c. 6-OHDA injected daily during the first 3 postnatal days led to a moderate decrease in rearing but was ineffective on other behavioural parameters. A dose of 100μg i. cer. (20, 30, 50μg on days 2, 4, 6 resp.) resulted in a considerable reduction in both rearing and acquisition of CAR, while 200μg i. cer. 6-OHDA (40, 60, 100μg on days 2, 4, 6) induced a marked impairment in rearing and acquisition of CAR, and a less pronounced decrease in crossing activity. No significant change was found in general motor activity. Increasing doses of 6-OHDA led to an 80–90% depletion in brain catecholamines and induced a content-related behavioural suppression in rearing and conditioned avoidance responding in particular. It is concluded that intracerebral administration of 6-OHDA into neonatal rats almost completely prevents the development of central catecholaminergic neuronal systems, and concomitantly the capability of acquiring conditioned avoidance behaviour, while reducing exploratory behaviour.

A contribution to the study of the architecture of the autonomic nervous system of the digestive tract of the rat.

Abstract: The distribution of aminergic and non-aminergic nerve fibres to the different constituents of the wall of the digestive tract in various regions is described. Aminergic fibres synapse with all nervous perikarya. Densely interlacing networks of nerve fibres are found in both layers of the tunica muscularis and in the lamina muscularis mucosae. A finely meshed plexus is observed in relation to the wall of the blood vessels in the wall of the gut. There are many fibres connecting the muscular and the vascular plexus. No nerve fibres have been observed in direct relation to the epithelium.

Effects of cortisol on evoked potentials and recovery cycles in the rat hypothalamus.

Abstract: A study was made of the effects of cortisol on hypothalamic potentials evoked in the rat by sensory and limbic stimulation. The hormone was found to increase the amplitude and to reduce the latency of the evoked potentials. It also enhanced the early facilitation in the recovery cycle of the response to septal stimulation, but prolonged the inhibitory phase in the cycle following septal or hippocampal stimulation. The present findings are discussed in relation to the effects of cortisol on the brain and its role in the neuroendocrine regulation of ACTH secretion.

The tyrosine-tryptophan-diagram in a longtime study with depressed patients.

Abstract: There were determined free plasma tyrosine and tryptophan spectral-photofluorometrically at 22 healthy controls and 81 depressed patients (13 of them were controlled in a long-time-study; mean time: 11 months, and 68 patients were controlled ambulant). The biochemical data were demonstrated in a tyrosine-tryptophan diagram and were correlated with the clinical behaviour of the patients. This correlation only was possible with the postulation of a balance between catecholamine-and indolamine metabolism. Three biochemical parameters are necessary. The values of 1. tyrosine that of 2. tryptophan and not only 3. the resulting quotient. With help of such demonstration we showed this tyrosine-tryptophan balance graphically. We think, that both catecholamine-and the indolamine-hypothesis of depression seem to have their availability.

An ultrastructural study of sympathetic ganglion satellite cells in the rat 1. Normal and x-ray irradiated satellite cells

Abstract: The ultrastructure of normal and irradiated satellite cells of the rat superior cervical ganglia was studied. Each neuron is closely and completely invested by satellite cell cytoplasm. The satellite cell cytoplasm usually contains a number of mitochondria, granular endoplasmic reticulum, Golgi apparatus, lysosome-like bodies, filaments, microtubules, lipid droplets, centriole and cilia. The satellite cell also encloses presynaptic nerve endings, and other nerve fibers. X-ray irradiation produces several changes in the satellite cells. These include: (a) increased nuclear density, (b) marked local widening of the perinuclear space, (c) dilation of granular endoplasmic reticulum and loss of attached ribosomes, (d) swelling of mitochondria with disorganization of mitochondrial cristae and loss of matrix, (e) increase in the number of vacuoles, and (f) increase in the number, size and contents of lysosome-like bodies.