Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Effect of synthetic substance P on monoaminergic mechanisms in brain. 0 76

Amphetamine-induced stereotyped behavior in animals is proposed as a model for schizophrenia. Chronic amphetamine administration produces stereotyped behavior and a paranoid schizophreniform syndrome in man, whereas in animals a behavioral sensitization to stereotypy is evoked. We now show that phenylethylamine (PEA), an amphetamine-like stimulant concentrated in the limbic system of human brain, produces stereotypy in rats with a behavioral sensitization when chronically administered. In comparing amphetamine-induced stereotypy with PEA-induced stereotypy, we found that the alpha-adrenergic blocking agents phentolamine and phenoxybenzamine selectively antagonize PEA stereotypy, whereas the beta-adrenergic blocking agent propranolol fails to alter significantly stereotypies evoked by PEA or amphetamine administration. Catecholamine depletion by alpha-methyl-p-tyrosine administration blocks stereotypies induced by both PEA amphetamine, whereas selective norepinephrine depletion antagonizes only PEA stereotypy; the amino acid precursors of both norepinephrine and dopamine potentiate stereotypies. Therefore, PEA-elicited stereotypy, but not amphetamine-elicited stereotypy, is dependent upon norepinephrine; the significance of this for the PEA animal model of schizophrenia is discussed.
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PMID:A new animal model for schizophrenia: interactions with adrenergic mechanisms. 20 65

The extended theory about a dysfunction of the serotoninergic system in depression and schizophrenia includes the hypothesis of a disturbance in the transport systems of tryptophan and tyrosine from blood to brain. It would be interesting to know if blood cells may be used as a model for the central transport mechanisms of these amino acids. After an oral load, the in vivo distribution of L-tryptophan (50 mg/kg) was studied in the blood plasma, in the different blood cells and its binding to plasma albumin, in six healthy, seven schizophrenic and two depressive subjects. In all the compartments studied, tryptophan reached a peak, 1--2 hours after the load. Before and after the load, the variation of the tryptophan concentration in the erythrocytes was parallel to the plasma free tryptophan, whereas the uptake of this amino acid was higher in leukocytes and thrombocytes than in erythrocytes. However, this model does not show differences between schizophrenic and normal subjects with regard to the transport of tryptophan and tyrosine in these cells.
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PMID:Distribution of tryptophan in erythrocytes, leukocytes and thrombocytes, and its binding to plasma albumin. 29 Jul 55

In order to investigate possible disturbances of the blood-brain transport mechanisms of monoamine precursors in manic-depressive illness and schizophrenia, we have measured the brain arterio-venous difference of DOPA, or 5-HTP, or tyrosine and tryptophan in 36 patients, during the infusion of either L-DOPA or L-5-HTP. The infusion lasted for 30 min, and blood was sampled during and immediately after the infusion, simultaneously in the femoral artery, the jugular vein and a vein of the arm. During the infusion of L-DOPA, manic patients have a higher extraction of L-DOPA than depressive patients and controls. During the infusion of L-5-HTP, pdpressive patients have a higher brain extraction of 5-HTP than manic or schizophrenic patients. In depressive patients, a small uptake of tryptophan correlated with a large outflow of tyrosine was observed. The opposite was seen in manic patients, with an outflow of tryptophan correlated with an uptake of tyrosine. In schizophrenics, there was an outflow of tryptophan and random variations of tyrosine. These brain arterio-venous differences were not correlated with arterio-venous differences for peripheral tissues. Taken together, these results are compatible with a disturbance of the blood-brain transport of amino acids precursors of monoamines in manic-depressive illness and schizophrenia.
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PMID:Blood-brain movements of tryptophan and tyrosine in manic-depressive illness and schizophrenia. 29 Jul 57

The uptake of tryptophan and tyrosine by the brain has been studied in 6 manic-depressive patients and in 8 schizophrenics. In an attempt to saturate the blood-brain transport mechanisms, this uptake has been evaluated by measuring the arteriovenous differences (arterial plasma-internal jugular plasma) of these two amino acids before and after perfusion with L-dopa and L-5-HTP. Considering a positive difference as an uptake and a negative one as an outflow, results show (1) in melancholia an uptake of tryptophan and an outflow of tyrosine; (2) in mania an uptake of tyrosine and an outflow of tryptophan, and (3) in schizophrenia an outflow of tryptophan accompanied with either an uptake or an outflow of tyrosine. In addition, the kinetics of tryptophan binding to plasma proteins and the ratio of tryptophan/tyrosine uptake are different in manic-depressive illness and in schizophrenia. These results support the view that a disturbance in the blood-brain transport mechanisms of tryptophan and tyrosine could be involved in the physiopathology of manic-depressive illness and schizophrenia.
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PMID:[Uptake of tryptophan and tyrosine in some cases of manic depressive psychosis and schizophrenia (author's transl)]. 61 4

Several recent data indicate the blood-brain transport of amino acids as a critical factor in the synthesis of monoamines. The complex, peripheral and central regulation of TP transport plays an essential role sine TP-hydroxylase is not a saturated enzyme. The hydroxylated derivatives 5-HTP and dopa are probably transported into the brain by similar mechanisms as their precursors TP and tyrosine, respectively. The maic-depressive patients show an increased uptake of administered L-5-HTP in the depressive phase, whereas L-dopa uptake is enhanced in the manic phase. Heuristically, we propose a biochemical model of manic-depressive psychosis in which an increased TP uptake causes alternation in the balance of monoaminergic system activity. Depression is possibly characterized by a hyperserotonergic and a relative hypocatecholaminergic activity. In contrast, mania is possibly determined by a hypercatecholaminergic (NA and DA) and a relative hyposerotonergic activity. The data offered by the physiology of monoamines, the semeiology and the biological alterations of the manic-depressive psychosis, as well as the monoaminergic and the electrolyte theory of manic-depressive psychosis. A diminution of the transport of TP with consequent increase of that of tyrosine represents a possible biochemical model of schizophrenia which may be well explained by a hyposerotonergic-hyperdopaminergic activity, with or without noradrenergic insufficiency. This model is compatible with our knowledge on the monoamine physiology, the biological alterations of schizophrenia, the therapeutical results as well as with the classical clinical notions (typology, intermediate syndromes and crossed heritance).
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PMID:The common pathophysiology of monaminergic psychoses: a new hypothesis. 77 59

The importance of amino acid transport across the blood-brain barrier as the limiting factor in the metabolism of monoamines has been emphasized by many recent publications. Particularly critical is the transport of tryptophan, since tryptophan hydroxylase is not saturated. This transport is regulated by complex mechanisms, both at the periphery (total and free plasmatic levels and levels of the other essential amino acids) and centraly (by feedback mechanism initiated at the pre- and post-synaptic levels). The hydroxylated derivatives of tryptophan and tyrosine, i.e. 5-HTP and L-DOPA, most probably share the same transport mechanism as these amino acids themselves. In manic-depressive patients, the uptake of L-5-HTP is increased during the depressive phase, while the uptake of L-DOPA, is increased during the manic phase. We suggest that an increase in the uptake of tryptophan may set off oscillations in all the monoaminergic systems, thus providing a biochemical model of manic-depressive psychosis. In terms of this model, melancholy would be due to a hyperserotoninergic syndrome together with a relative hypocatecholaminergic syndrome. Mania would be due to a homogeneous hypercatecholaminergic syndrome together with a relative hyposerotoninergic syndrome. Such a model is compatible with present knowledge of the physiology of monoamines, of the semeiology and biological disturbances of manic-depressive psychosis, and of the treatment of this disease. It reconciles the monoaminergic and ionic theories of the disease better than other existing hypotheses. A reduced transport of tryptophan with a secondary increase in the transport ot tyrosine provides a conceivable model for schizophrenia. Indeed, a serotoninergic hypoactivity coupled with a dopaminergic hyperactivity, with or without a noradrenergic deficiency, would account for the semeiology quite adequately. This model too would be compatible with present knowledge of monoamine physiology, of the biochemical disturbances underlying schizophrenia and of the mode of action of anti-psychotic drugs. This unitarian heuristic concept of the monoaminergic psychoses would be in better agreement with the classic clinical data concerning this disease (typology intermediate syndromes and crossed heredity).
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PMID:[Hypothetical concept: the physiopathological entity of monoaminergic psychoses]. 108 12

Changes in dopamine (DA) turnover have been studied in rats after treatment with pimozide and/or gabergic drugs such as beta-(p-chlorophenyl)-GABA and aminooxyacetic acid using the tyrosine-hydroxylase inhibitor alpha-methyltyrosine and methylester (H44/68). The changes in DA levels were determined by quantitative microfluorimetrical analysis of the fluorescence in various DA terminal systems. Beta-(p-chlorophenyl)-GABA (5--20 mg/kg) and aminooxyacetic acid (25 mg/kg) counteracted the pimozide (1 mg/kg) induced increase in DA turnover in subcortical and cortical limbic regions but not in the caput of the caudatus. These findings indicate the existence of a strong and preferential inhibitory gabergic control of the mesolimbic DA neurons and offer the possibility of improving the treatment of schizophrenia provided that limbic DA receptors are involved in this disease. If so, lesions of gabergic pathways may exist in the schizophrenic brain.
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PMID:Evidence for an inhibitory gabergic control of the meso-limbic dopamine neurons: possibility of improving treatment of schizophrenia by combined treatment with neuroleptics and gabergic drugs. 116 Apr 12

An alteration of dopaminergic transmission in the brain has been proposed for schizophrenia. To explore this, the rate constant for the intransport of L-tyrosine across the blood-brain barrier in healthy controls and in patients with schizophrenia (DSM-III-R) was determined with PET and L-[1-11C] tyrosine as the tracer. Kinetics for tyrosine transport were determined according to a two-compartment model using radioactivity data of arterial blood and brain tissue sampled between 1 and 3.5 min after a bolus injection of L-[1-11C] tyrosine. Radioactivity was measured every second in the blood and in 10-sec intervals in the brain tissue. In the normal controls the brain intransport rate constant for tyrosine was 0.052 ml/g/min with an influx rate of 2.97 nmol/g/min. The patients had a similar intransport rate constant (0.045 ml/g/min) but a lower influx rate of tyrosine 1.95 nmol/g/min (p less than 0.05). The patients' tyrosine concentrations in the blood were lower. For data sampled between 5 and 25 min, the net accumulation rate of tyrosine into the brain was 0.015 ml/g/min in the controls which did not differ to the patients' rate. However, the net utilization of tyrosine was lower in the patients (0.672 nmol/g/min) than in the controls (0.883 nmol/g/min) despite similar tissue concentrations of tyrosine.
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PMID:The transport of tyrosine into the human brain as determined with L-[1-11C]tyrosine and PET. 194 Nov 37

Basal serum amino acids (including central monoamine precursors), central monoamines, and hormones were studied in schizophrenic patients (drug-naive; n = 20; drug-withdrawn for 3 or more days, n = 67; neuroleptic-treated, n = 23) and healthy subjects (n = 90) to answer the following questions: (1) Do neuroleptic-withdrawn and neuroleptic-naive patients differ on these serum measures? (2) What are the effects of neuroleptic treatment on these measures? (3) On which variables do drug-free and neuroleptic-treated patients differ? Because serum amino acid, central monoamine, and hormone levels were similar in drug-naive and drug-withdrawn patients, data from these groups ("drug-free") were combined and compared to those of healthy subjects and neuroleptic-treated patients. Asparagine, citrulline, phenylalanine, and cysteine were higher, while tyrosine, tryptophan, and the ratio of tryptophan to competing amino acids were significantly lower in drug-free schizophrenic patients than in healthy subjects. Dopamine was increased, and melatonin and thyroid hormones were decreased in drug-free schizophrenic patients compared to healthy subjects. Norepinephrine, epinephrine, and prolactin were higher in neuroleptic-treated men compared to drug-free male patients or healthy men. These results are consistent with the hypothesis of dopaminergic overactivity in schizophrenia, which might be caused by altered amino acid precursor availability and could be related to the decrease in melatonin and reduction in thyroid hormone levels.
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PMID:Serum amino acids, central monoamines, and hormones in drug-naive, drug-free, and neuroleptic-treated schizophrenic patients and healthy subjects. 198 23


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