Brain amine metabolism

Investigations in recent years have indicated a possible relationship between brain amine metabolism and Parkinson s disease. Dopamine, noradrenaline, and serotonin have a characteristic distribution in the human brain. Dopamine is found in especially high concentration in the nuclei of the neostriatum, i.e. in the caudate nucleus and putamen noradrenaline and serotonin predominantly in the hypothalamus, in the central grey matter, and in the reticular formation. The brain content of these amines is reduced in patients... 

Brain Amine Metabolism in Some Neurological and Psychiatric Disorders... 

While the determination of lumbar CSF amine metabolites has considerable advantages over urine or blood determinations in the study of human brain amine metabolism, abnormal values do not necessarily indicate abnormal metabolism of the precursors in the brain. Abnormality of transport of the acidic metabolites from brain to CSF, from CSF to blood or from the ventricles to the lumbar sac could also be responsible. Ventricular levels are much higher than lumbar levels [71, 82, 88] as an active process of transport of the acids from the CSF to the blood occurs together with the movement of CSF down the spinal... 

However, notwithstanding these limitations the determination of amine metabolites in the lumbar CSF is at present the most practical and fruitful method for the study of human brain amine metabolism. 

Parkinson s disease is the brain disease in which clearest evidence has been obtained that a disturbance of brain amine metabolism plays a major role in the development of symptoms. It is also a striking example of a common brain disease of which a knowledge of the biochemical disturbance has led to the prediction of a successful rational therapy. Some useful general accounts of developments in this area have recently appeared [107, 108, 109],... 

Drug treatment of Parkinson s disease in relation to the disturbance of brain amine metabolism... 

To summarize, there are many indications of relationships between brain amines and drugs causing states with similarities to schizophrenia and some information on the exacerbation of schizophrenia by drugs which can influence amine metabolism. However, direct evidence concerning abnormal brain amine metabolism in spontaneous schizophrenia is not yet available. 

A number of other rare disturbances of aromatic amino acid metabolism associated with mental defect and usually with evidence of inheritance have been reported (see ref. 419 for review) and might well also lead to disturbed brain amine metabolism, e.g. tyrosinaemia, increased urinary dopa with dwarfism, tryptophanuria, hydroxykynureninuria and hyper-calcaemia with indicanuria. 

Perhaps because of these effects on metabolism of brain amines CYP2D6 status has been linked to personality traits [34]. These personality traits are themselves associated with tobacco dependence and hence provide another possible mechanism finking allelic variation at the CYP2D6 locus to smoking behavior. 

Okonmah AD, Brown JW, Blyden GT, Soliman KF. (1988). Prenatal effects of acute harmaline exposure on fetal brain biogenic amine metabolism. Pharmacology. 37(3) 203-8. 

The principal groups of antidepressants available today are all presumed to exert their action via alteration of brain monoamine metabolism. These amines include norepinephrine, dopamine, and serotonin. The involvement of catecholamines in the pathogenesis of depression was invoked as early as 1965. A deficiency in brain serotonin was theorized in 1967, while a role for dopamine in depression was formally proposed in 1975. The drugs that are used to treat depression basically act to increase neurotransmitter concentration in the synaptic cleft either by (1) decreasing neurotransmitter degradation or (2) inhibiting neurotransmitter reuptake. 

Moore RY (1970) Brain lesions and amine metabolism. Rev Neurobiol 73 67-71. 

Biology - Two symposia -> on brain amines have been summarized and another3 has been published in full. A review on the metabolism of noradrenaline (NA) in the central nervous system has appeared. Krnjevic has written a useful review on chemical transmission in the central nervous system. 

Subhash MN, Padmashree TS. 1991. Effect of manganese on biogenic amine metabolism in regions of the rat brain. Food Chem Toxicol 29 579-582. 

The greater importance of 0-methylation in the inactivation of circulating catechol amines is due to the fact that, in the liver, where most of the breakdown takes place, the activity of catechol 0-methyltransferase is very much higher than that of monoamine oxidase. This relationship does not, however, apply to all other organs in the heart, for instance, monoamine oxidase is about five times as active as the 0-methyltransferase, and monoamine oxidase also plays a part in catechol amine metabolism in the brain. 

Monoamine oxidase inhibitors The MAO inhibitors increase brain amine levels by interfering with their metabolism in the nerve endings, resulting in an increase in the vesicular stores of norepinephrine and serotonin. When neuronal activity discharges the vesicles, increased amounts of the amines are released, enhancing the actions of these neurotransmitters. 

Folate seems to have a significant, but poorly defined, role in brain function. It is concentrated two- to fourfold in CSF, as opposed to serum, by a saturable, presumably active process (Lipton et al., 1979). Brain levels decrease less rapidly than serum and peripheral nerve levels during folate depletion (Fehling, 1976). Dihydrofolate reductase is present in rat brain (Pollock and Kaufman, 1978), and brain folate depletion may impair central nucleic acid metabolism (Haltia, 1970). Folate is associated with central amine metabolism. It is concentrated in the synaptic region (McClain et al., 1975) and may function as a coenzyme in monoamine biosynthesis. Korevaar et al. (1973) found the highest brain folate levels in the median raphe and corpus striatum, areas also rich in serotonin neurons. 

Imipramine blocked the uptake of dopamine at central aminergic neurons in the rat Lithium inhibited the electrically-induced release of NE and 5" in brain slices 3 and did not interfere with the transfer rate of Ma from blood to brain tissue. Data were reported which suggested that the therapeutic effect of electroshock treatment may be due to increased levels of brain amines 5 or to an increase in NE turnover rate . In a study of catecholamine turnover rates in mouse brain it was found that neuroleptics have a predominant influence on dopamine metabolism while antidepressants selectively affect NE metabolism, a higher rate of NE synthesis was found in the forebrain of "mouse-killing" rats over that of controls Imipramine blocked the muricidal behaviour9 and also lowered NE turnover . 

Despite the fact that these various sub-compartments are identifiable in functional and not morphologic terms, the probability of their existence makes it no longer possible to attach significance to alterations in total levels of the amines as correlates of altered function. Therefore, the effect of many centrally acting drugs on total levels of brain amines must now be re-examined in the light of dynamic aspects of monoamine metabolism in the brain, since the storage levels of these amines are not static but reflect dynamic equilibria between their rates of formation and their rates of utilization ... 

The brain contains all the enzymes necessary for the synthesis of the amines from their precursors tyrosine and tryptophan and for their destruction. The immediate precursors, dopa [43] and 5HTP [44] and also the more distant precursors L-tyrosine and L-tryptophan can penetrate to the brain when given systemically and therefore can increase brain amine concentrations. However, catecholamines or 5HT synthesized or introduced peripherally are generally found to penetrate the blood-brain barrier only slightly [45,46] although one group reports uptake and very rapid metabolism in the brain of 5HT given peripherally to rats [47]. 

Even in the absence of the above extracerebral mechanisms by which abnormal CSF HVA and 5HIAA may arise, CSF levels of these substances, while reflecting brain metabolism of their parent amines, do not allow a full balance sheet to be drawn up for any brain amine. This is clear from Figure 5.2. For example, estimation of the ratio of intraneuronal to extraneuronal metabolism of a catecholamine requires determination of the ratio of its deaminated to its 0-methylated metabolites [40, 41]. Only one brief report [97] has appeared on the... 

Thus, while brain amine disturbance in Parkinson s disease is well authenticated, evidence for urinary abnormalities is not striking and is unlikely to reflect metabolic disturbances of primary importance. 

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