Moussa Youdim

Does brain 5-HIAA indicate serotonin release or monoamine oxidase activity?

The question of whether serotonin is deaminated by MAO before it can be released or after release has occurred was investigated by studying the 5-HT behavioral syndrome in acutely reserpinized rats. The release of serotonin from vesicles by reserpine does not produce the serotonin behavioral syndrome which is an in vivo index of serotonin release and receptor activation. However, if rats are first pretreated with a nonselective monoamine oxidase inhibitor (e.g., tranylcypromine), the injection of reserpine is followed by symptoms which are characteristic of the behavioral syndrome including forepaw treading, hindlimb abduction and head weaving. Neither selective MAO-A or -B inhibition with clorgyline or deprenyl, respectively, nor inhibition of serotonin reuptake with fluoxetine prior to reserpine produced the serotonin behavioral syndrome. However, the combination of clorgyline and deprenyl followed by reserpine does so. These behavioral data along with neurochemical analyses of serotonin and 5-hydroxyindoleacetic acid levels lead to the conclusion that serotonin does not have to be released before it is metabolized to 5-hydroxyindoleacetic acid. Consequently, the levels of 5-hydroxyindoleacetic acid in brain reflect MAO activity and not serotonin release or utilization.

Contrasting monoamine oxidase activity and tyramine induced catecholamine release in PC12 and chromaffin cells

PC12 (phaeochromocytoma derived) cells possess the catecholamine synthesizing enzymes as well as the ability to store and release the catecholamines in response to K+. However, their monoamine oxidase activity and catecholamine release in response to tyramine has not been examined previously. PC12 cells have monoamine oxidase activity which oxidizes type A (noradrenaline and serotonin) and type A-B (dopamine, tyramine and kynuramine) substrates, and is selectively inhibited by clorgyline (IC50 approximately 10(-6) M). In contrast, PC12 cell monoamine oxidase hardly oxidizes phenylethylamine a type B substrate, and is relatively insensitive to inhibition by the selective monoamine oxidase type B inhibitor, 1-deprenyl (IC50 approximately 10(-6) M). By the above criteria it is apparent that the monoamine oxidase in PC12 is solely type A. The kinetics of the oxidase are similar to those of monoamine oxidase type A reported in other tissues including the adrenergic neuron, having apparent Km values of 400, 280, 170 and 227 microM for noradrenaline, dopamine, serotonin and tyramine. The apparent Km value for phenylethylamine is 235 microM. On the other hand, isolated chromaffin cells have the B form of monoamine oxidase with high affinity (Km approximately 25 microM) for phenylethylamine and low affinities for noradrenaline (Km approximately 1100 microM) and adrenaline (Km approximately 1700 microM). This enzyme form is selectively inactivated by the monoamine oxidase type B inhibitor, 1-deprenyl. In similar fashion to peripheral adrenergic neurons, PC12 cells share the capacity to express a tyramine releasable pool of catecholamines, a property entirely lacking in mature cultured chromaffin cells, even though the latter cells are capable of taking up tyramine by a cocaine sensitive process.(ABSTRACT TRUNCATED AT 250 WORDS)

Monoaminergic involvement in the pharmacological actions of buspirone

1 Buspirone, MJ‐13805 and MJ‐13653 did not produce a ‘5‐hydroxytryptamine (5‐HT) syndrome’ in rats at doses up to 20 mg kg−1. 2 These drugs were very weak 5‐HT uptake blockers (IC50 ≫ 10 μM) compared to drugs such as chlorimipramine. 3 These drugs did not inhibit either monoamine oxidase (MAO)‐A or MAO‐B. 4 The Ki values for these agents as inhibitors of [3H]‐5‐HT and [3H]‐ketanserin binding to rat frontal cortex or hippocampal membranes were in the μM range, well above the brain concentrations achieved after an oral dose of 25 mg kg−1. 5 Parenterally administered buspirone blocked apomorphine‐induced sterotypy, inhibited the 5‐HT syndrome elicited by 5‐methoxy‐N,N‐dimethyltryptamine, and delayed the onset of p‐chloroamphetamine induced behaviours.

Hormone Secretion by Exocytosis with Emphasis on Information from the Chromaffin Cell System

Publisher Summary This chapter discusses hormone secretion by exocytosis with an emphasis on information from the chromaffin cell system. Exocytosis is the general mechanism by which many hormones, transmitters, enzymes, and other special proteins and peptides are secreted from cells. Exocytosis means that the chemical species to be secreted is stored in a secretory vesicle, which, upon the appropriate stimulus, fuses with the cell membrane and deposits the vesicle contents outside the cell. The “handmaiden” of this process is usually calcium. In many cases, the ultimate signal for exocytosis seems to be an increase in the intracellular free calcium ion concentration. For many reasons, the chromaffin cell is the very best vantage point from which to examine the hormone-secretion process. From a biochemical viewpoint, the chromaffin cell has no peer, subcellular fractionation is simple, and the cells are easily cultured. Chromaffin cells in the adrenal medulla are joined and electrically coupled into cords of cells surrounded in the intact gland by an abundant fenestrated capillary bed.

The MPTP-Induced Parkinsonian Syndrome in the Goldfish Is Associated with Major Cell Destruction in the Forebrain and Subtle Changes in the Optic Tectum☆

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can induce a parkinsonian syndrome in humans and nonhuman primates, which is susceptible to treatment and prevention by drugs such as L-DOPA and L-deprenyl. Recently, we have reported that MPTP can also cause a parkinsonian syndrome in the common goldfish, which appears to faithfully mirror the neurochemical and behavioral aspects of the action of MPTP in the higher vertebrates. In addition, we recently identified the likely teleost equivalent of the substantia nigra in the goldfish forebrain, the nucleus pars medialis, on the basis of its destruction by MPTP and selective protection by the MAO-B blocker L-deprenyl. In the present work we substantiate this conclusion by examining tissue destruction the goldfish forebrain at increasing MPTP concentrations, up to the the LD50 of 200 mg/kg. In addition, we show that at the highest MPTP dose subtle changes also occur with low frequency in nondopaminergic cells in the optic tectum, and in ependymal cells lining the midbrain ventricle. The effects on ependymal cells are similar to those previously noted in the forebrain. We conclude that the goldfish model continues to faithfully mimic the histologic pattern of parkinsonian tissue destruction engendered by MPTP in primate models.

The role of monoamine oxidase A in the metabolism and function of noradrenaline and serotonin

Monoamine oxidase (MAO) inhibitors were among the first psychotropic drugs to be discovered and introduced into clinical use either alone or in combination with serotonin (5-hydroxytryptamine) (5-HT) precursors for the treatment of depressive illness (Youdim & Finberg, 1982). The result of MAO inhibition is that brain 5-HT and noradrenaline (NA) are elevated and the pharmacological effects of indirectly acting amines of dietary origin (e.g. tyramine and phenylethylamine) are potentiated, whether or not the indirectly acting amines are substrates for MAO. Perhaps the most common effect is the hypertensive response produced by dietary tyramine in individuals medicated with MAO inhibitors (MAOIs). Since this syndrome was first recognized in patients who ingested certain cheeses which contained high levels of tyramine, the syndrome is referred to as the ‘cheese effect’. The ‘cheese effect’ occurs because these indirectly acting amines, which are also substrates for the neurotransmitter uptake system, release noradrenaline (NA) into neuronal cytoplasm where it is normally deaminated by MAO before egress from the neurone occurs.

Contribution of Intracellular Non-Haem Iron, NF-kB Activation and Inflammatory Responses to Neurodegeneration in Parkinson’s Disease: Prospects for Neuroprotection

Parkinson’s Disease (PD) involves the progressive degeneration of dopamine neuron cell bodies arising in the substantia nigra and extending through its terminals into the striatum. The disease is best described as a deficiency of striatal dopamine. The mechanism of neurodegeneration is an enigma in spite of the many hypothesis and efforts made so far to identify it (Youdim and Riederer, 1997; Jenner, 1998). Nevertheless, in the past few years much has been learnt about the chemical pathology of PD, especially in the substantia nigra pars compacta (SNpc). The most valid current hypothesis concerning the pathogenesis of PD is an on going oxidative stress (OS) which expresses itself with biochemical changes selectively in SNpc (Riederer et al., 1989; Youdim et al., 1993a,b; Gerlach et al., 1994; Gotz et al., 1994; Jenner and Olanow, 1996; Olanow and Youdim, 1996; Youdim and Riederer, 1997; Jenner, 1998).