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Section I: Cellular and Molecular Neurobiology 12. Biogenic Amine Neurotransmitters Part 9 of 11 Jack C. Waymire, Ph.D.

Inactivation of MA Neurotransmitters by Reuptake and Metabolism

Reuptake of MA Neurotransmitters

A low affinity uptake of monoamines into surrounding glial cells also inactivates released monoamines. Because this process acts only at very high concentrations of monoamines, it is believed to only come into play when the concentration of released neurotransmitter is very high.

A portion of released catecholamines diffuse to the extracellular space where monoamine oxidase (MAO) and/or catechol-0-methyl-transferase (COMT) eventually catabolize it. This route of inactivation is more prominent following extremely high levels of catecholaminergic neuronal activity.

Metabolism of MA Neurotransmitters

Monoamine Oxidase (MAO): This metabolic enzyme is located on the outer membrane of the mitochondrion and metabolizes DA, NE and 5-HT by oxidative deamination of (see Figure 12.12) to the corresponding aldehyde (DHPA, DHPGA and 5HIAA, respectively). DHPA and PHPGA are aldehyde intermediates that must be further metabolized by aldehyde reductase or dehydrogenase to alcohols and acids, respectively. These metabolites are excreted (see Table VI), or further metabolized by methylation through the action of catechol- O-methyltransferase and then excreted (see below). Pargyline, an irreversable inhibitor of MAO, blocks monoamine degradation.

Figure 12.12a	Figure 12.12b	Figure 12.12c
The deamination of three monoamine by mitochondrial MAO.

Catechol-O -methyl-transferase (COMT): This extraneuronal enzyme inactivates catecholamines by methylation of the hydroxyls on the catechol ring. COMT methylates either catecholamines that have already been metabolized by MAO or those that have not. The metabolites of catecholamines are shown in Table VI.

Measurement of MA metabolites in CSF, blood or urine provides a useful clinical index of the rate of release or turnover of MA neurotransmitters. Metabolites of catecholamines and serotonin are assayed in the CSF to obtain an index of brain metabolites. This method has been only modestly useful in determining the role of a specific MA neurotransmitters in brain disorders. Likewise, specific catecholamine metabolites in urine or the blood provide an index of peripheral sympathetic neurons and adrenal medullary catecholamines. The metabolites that are routinely measured clinically to assess CNS and peripheral catecholamine function are summarized in Table VI. Two CSF metabolites provide a measure of central DA function: 1) HVA, a methylated DA metabolite (metabolized by both MAO and COMT), and 2) DOPAC, an un-methylated metabolite, (metabolized by only MAO). The CSF metabolite that is measured to assess central NE function is MHPG, a methylated NE metabolite (metabolized by MAO and COMT). The metabolite that provides the best index of autonomic nervous system activity is VMA, a methylated NE metabolite (metabolized by both MAO and COMT). Metanephrine levels are monitored to assess the relative activity of the adrenal medulla or a tumor of this tissue, phaeochromocytoma. 5-HIAA reflects the activity of 5-HT cells.

Histamine: The metabolism of HA is somewhat different than the other MA. HA is taken up into cells where it is first methylated by histamine methyltransferase (HMT) to form telemethylhistamine. MAO subsequently oxidizes telemethylhistamine to the histamine metabolite, telemethylimadazole (TMI).
	Figure 12.13 The metabolism of HA through methylation and deamination.

DOPAC= dihydroxyphenylacetic acid HVA=homovanillic acid VMA=vanillymandelic MHPG=3-methoxy,4-hydroxyphenylethylene glycol 5-HIAA=5-hydroxyindoleacetic acid TMI = telemethylimadazole

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Cross Reference: Links for Dopamine

Cross Reference: Links for Norepinephrine

Cross Reference: Links for Serotonin

Cross Reference: Links for Histamine