Biomedical subjects
A Carlsson
Publications and source records attributed to A Carlsson.
Influence of GABA and GABA-like drugs on monoaminergic mechanisms.
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Dopaminergic autoreceptors: background and implications.
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Potentiation by metyrosine of thioridazine effects in chronic schizophrenics. A long-term trial using double-blind crossover technique.
Four patients with chronic schizophrenia of stationary character were studied in order to titrate the lowest dose of thioridazine necessary for symptomatic control when the drug is given in combination with the inhibitor of catecholamine synthesis, metyrosine. The study showed 15% to 50% of the pretrial dose level of thioridazine hydrochloride was effective. In the present trial, the 779704 combination was maintained without any alterations in dosage for six months, and the therapeutic effect persisted unchanged. This treatment period was terminated by a double-blind crossover design, and the activity of metyrosine was corroborated in all cases. Plasma drug concentrations and cerebrospinal fluid amine metabolites were measured. The data indicate that schizophrenic symptoms can be profoundly influenced by changes in catecholamine synthesis. Catecholamine-carrying neurons thus seem to be fundamentally involved in those brain functions that are disturbed in schizophrenia. The clinical usefulness of metyrosine in combination with neuroleptic agents deserves more extensive investigation.
Potentiation of the antidepressant action of clomipramine by tryptophan.
In a double-blind study of 24 patients with endogenous depressiona group treated with clomipramine hydrochloride (chlorimipramine) plus tryptophan was compared with a group treated with clomipramine plus placebo. The sum of the ratings for depressed mood, suicidal intent, depressive thought content, and anxiety showed a more rapid improvement in the former group, the difference being already significant after 12 days of treatment. On the other hand, the ratings for retardation decreased about equally in both groups during the three-week treatment period. Side-effect ratings showed no significant increase but seemed to be partly influenced by the improvement of depressive symptoms. Plasma levels of clomipramine appeared to reach a plateau within a few days, whereas the monodesmethylated metabolite continued to rise for a longer period of time, and reached considerably higher values than the parent compound. In the tryptophan group the degree of improvement seemed to be positively correlated to these levels, suggesting that further improvement might have been reached in some patients by increasing the dose of clomipramine. The levels of 5-hydroxyindoleacetic acid in the cerebrospinal fluid appeared to be reduced by clomipramine administration. This effect was prevented by the additional treatment with tryptophan.
Recovery of dopamine in peripheral adrenergic nerves after reserpine treatment.
The endogenous levels of dopamine (DA) in the rat heart and submaxillary gland after a single, large dose of reserpine (10 mg/kg i.p.) were reduced to near zero within 1 h and were restored to normal within 48 h, while the noradrenaline (NA) levels reacted much more slowly. The data suggest that newly formed DA is rapidly taken up by the reserpinesensitive mechanism of the amine storage granules. The more rapid restoration of DA than of NA levels may be due to preferential release of newly formed NA by the nerve impulse. Electrical stimulation of the cervical sympathetic with 5 Hz for 30 min 4 h after the administration of reserpine increased the DA level of the submaxillary gland of the stimulated side, suggesting an increased tyrosine hydroxylase activity during stimulation, also in nerve terminals affected by reserpine. The use of an inhibitor of monoamine oxidase (pargyline) and/or an inhibitor of dopamine beta-hydroxylase (FLA-63) did not significantly alter the increase of DA following nerve stimulation, suggesting DA was protected by granular uptake. The stimulation-induced increase in DA was, however, much less in reserpine-treated than in normal animals, demonstrating the importance of the reserpine-sensitive uptake mechanisms for preserving newly formed DA.
Suppression of ethanol-induced locomotor stimulation by GABA-like drugs.
Ethanol (2.4 g/kg) was given intraperitoneally to mice and was found to cause a marked increase in spontaneous locomotor activity. When mice were pretreated with low doses of agents which mimic or augment the action of GABA (gamma-hydroxybutyric acid, baclophen, or aminooxyacetic acid) the ethanol-induced locomotor stimulation was completely eliminated; Baclophen (10 mg/kg) was found to cause an initial increase followed by a later decrease in synthesis of catecholamines, as measured by the accumulation of dopa after inhibition of central aromatic L-amino acid decarboxylase, in dopamine-rich areas of rat brain. These data are consistent with previous findings that baclophen, as well as other agents which enhance the activity of GABA systems, reduce the firing of dopamine neurons, thus causing enhanced synthesis of dopamine via feedback mechanisms. These findings also indicate a potential interaction between GABA-like drugs and alcohol in man, and may be of heuristic value in the treatment of chronic alcoholism. The possibility that the mechanism of the inhibition of ethanol-induced locomotor stimulation by GABA-like drugs may be due to a selective interference with ethanol-induced dopamine release is discussed.
The role of intraneuronal amine levels in the feedback control of dopamine, noradrenaline and 5-hydroxytryptamine synthesis in rat brain.
The influence of varying brain levels of dopamine, noradrenaline and 5-HT on their respective synthesis rates has been investigated. The first step in monoamine synthesis was studied in vivo by measuring the accumulation of dopa and 5-hydroxytryptophan after inhibition of the aromatic L-amino acid decarboxylase. Variations in monoamine levels were obtained by combined treatment with inhibitors of the decarboxylase (NSD 1015 or Ro 4-4602) and of monoamine oxidase (pargyline). An increase in monoamine levels by pargyline was found to inhibit the synthesis of dopamine, noradrenaline and 5-HT. Conversely, a decrease in monoamine levels induced by the decarboxylase inhibitor Ro 4-4602 appeared to stimulate dopamine and noradrenaline synthesis but had no effect on 5-HT synthesis. The influence of varying levels of dopamine and noradrenaline on the synthesis of these amines could still be demonstrated after blockade of dopamine receptos and of alpha-adrenergic (noradrenaline) receptors by haloperidol, suggesting that the mechanism involved in this feedback control is mediated via end-product inhibition of tyrosine hydroxylase. On the other hand, the stimulating influence of haloperidol on the synthesis of catecholamines does not seem to be directly related to changes in catecholamine levels. It is concluded that the short-term control of catecholamine synthesis presumably involves two independent feedback mechanisms, one intraneuronal mechanism operating via end-product inhibition, and one synaptic mechanism mediated via dopamine and noradrenaline receptors, respectively. Both pre- and postsynaptic receptors may be involved in the latter mechanism.
Distribution of dopamine in the rat cerebral cortex.
The rat cerebral neocortex was sectioned by 3 transverse cuts and analyzed for dopamine and noradrenaline. Dopamine concentration decreased gradually from the rostral (97 +/- 4 ng/g) to the caudal (59 +/- 2 ng/g) end of the neocortex. Also, the noradrenaline concentration was highest in the rostral part (269 +/- 6 ng/g) and decreased gradually reaching a concentration of 238 +/- 3 ng/g in the caudal part. Since the quotient dopamine/noradrenaline showed similar changes in the neocortex parts investigated the data support the view that dopamine serves as a transmitter in cortical neurons apart from being a precursor for noradrenaline.
Influence of age and time interval between death and autopsy on dopamine and 3-methoxytyramine levels in human basal ganglia.
The caudate nuclei and putamens of 30 human brains were analyzed for dopamine and its metabolite 3-methoxytyramine, most of which was presumably formed from dopamine postmortally. It was found that dopamine and the sum (dopamine + methoxytyramine) but not methoxytyramine declined with the time interval between death and autopsy as well as with age.
Effect of synthetic substance P on monoaminergic mechanisms in brain.
Synthetic substance P has been discovered to stimulate significantly the formation of dopa in the limbic, striatum, hemisphere and diencephalon regions of the brain and the lower brain stem. There was no effect upon 5-hydroxytryptophan formation or on tryptophan or tyrosine levels. After inhibition of monoamine synthesis by N'-(DL-SERYL)-N2-(2, 3, 4-trihydroxybenzyl)hydrazine, substance P significantly accelerated the disappearance of dopamine, noradrenaline and 5-hydroxytryptamine. Substance P appears to stimulate monoaminergic neurons in the brain and to serve as an excitatory transmitter in nerve terminals impinging upon dopaminergic cell bodies. A similar stimulation of noradrenaline and 5-hydroxytryptamine indicate a similar transmitter role for noradrenergic and serotonergic neurons. These data strengthen questions about the possible clinical influence of substance P in disease states involving monoaminergic mechanisms including Parkinsonism and schizophrenia.
Patellar giant cell tumor.
Primary patellar neoplasms are distinctly unusual. A rare case of patellar giant cell tumor which caused clinical, radiographic, and histologic confusion is described. The lesion progressed rapidly, underscoring the potential aggressive behavior of the tumor. Amputation is the preferred treatment. A review of the literature is also presented.
The contribution of drug research to investigating the nature of endogenous depression.
A relationship between brain monamines and endogenous depression is suggested by observations on the mode of action of drugs producing or alleviating depressive symptoms. For example, reserpine is capable of faithfully mimicking the clinical picture of endogenous depression, which may be related to monoamine depletion. On the other hand, antidepressant drugs, e.g. the monoamine oxidase inhibitors, the tricyclic antidepressants and the monoamine precursors appear to increase the availability of monoamines at postsynaptic receptor sites. The different classes of antidepressant agents in general appear to potentiate each other's actions, according to animal data and clinical observations. Studies on the mode of action of tricyclic antidepressants with different profiles and on monoamine precursors suggest that 5-hydroxytryptamine is primarily involved in the control of mood, and noradrenaline in psychomotor activity. Clincial investigations initiated by the drug studies have demonstrated changes in monoamine metabolism in endogenous depression. The available evidence thus suggests a causal relationship between disturbances in monoamine metabolism and depression.
Some aspects of dopamine in the basal ganglia.
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Letter: Potentiation of antidepressant action of clomipramine by tryptophan.
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Functional and biochemical aspects of catecholamine metabolism in brain under hypoxia.
Animals exposed to 6% oxygen showed a partial inhibition of the rate of tyrosine hydroxylation and a blockade of the conditioned avoidance response. The behavioral disruption was suggested to result, at least in part, from a dopaminergic disturbance, since the behavior was restored by the administration of DOPA or apomorphine but not by 5-hydroxytryptophan. Biochemical data showed a selective retardation in brain dopamine (DA) disappearance after synthesis inhibition. Methoxytyramine formation was markedly retarded. Analysis of this effect indicated that the decreased DA turnover was related to the release of transmitter rather than to an effect on catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO). In addition, there was evidence for a partial inhibition of MAO activity by hypoxia as well as a decreased activity of dopamine-betahydroxylase. It was concluded that the disruption of behavior was related to decreased dopaminergic receptor activation and that decreased synthesis played at most a contributory role.
Studies on the synthesis and subcellular distribution of dopamine in the rat adrenal medulla.
Rats received intravenous injections of 3H-tyrosine and were killed at various time intervals thereafter. 3H-dopamine (DA) in the adrenals reached a maximum within 1.5 min after the administration of 3h=tyrosine. From the 15th min it disappeared with an apparent half life of 90 min. 3H-Adrenaline (A) plus 3H-noradrenaline(NA) increased much more slowly and reached a plateau 120-240 min after the injection. The approximate synthesis rate of adrenal A plus NA, calculated from the specific activity curves, ranged from 0.3 to 2.2 nmoles/h per kg b.w. The highest value was noted the first few minutes, the lowest 1-2 hrs after the administration of 3H-tyrosine. In some experiments subcellular fractionation of the adrenals was performed. In untreated animals the amount of DA and A plus NA recovered from the supernatant fraction was about 10 and 8 per cent, respectively, of the total amount recovered from the supernatant and particulate fractions. In the adrenals of animals receiving 3H-tyrosine 3.75 or 60 min beforehand these figures were significantly elevated whereas the DA and A plus NA of the particulate fraction did not deviate significantly from control values. The specific activities of 3H-DA were the same in the supernatant and particulate fractions within 3.75 min after the injection of 3H-tyrosine.
Attempts to measure endogenous levels of dopa and 5-hydroxytryptophan in rat brain.
We have used previously published analytical methods of high sensitivity, developed in our laboratory, in an attempt to detect endogenous dopa and 5-hydroxytryptophan (5-HTP) in normal rat brain. In the brains of rats killed by decapitation we were unable to detect any dopa and found only a few ng/g of 5-HTP. Higher levels were found in the brains of rats killed by exposing their heads to microwaves. The levels of dopa found under these conditions varied considerably between different rat strains, and also between different experiments on the same strain, ranging between 2.5 and 13.8 ng/g. True resting levels may be lower than those observed because the procedure necessitated a short-lasting immobilization stress which increased the dopa (but not 5-HTP) levels. The 5-HTP levels were also variable and ranged between 5 and 25 ng/g. The highest levels of dopa and 5-HTP were found in the Japanese Wistar strain with spontaneous hypertension. Some analytical pitfalls are pointed out.