Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males.

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Aggressive Behavior and Altered Amounts of Brain Serotonin and Norepinephrine in Mice Lacking MAOA

Cloning of MAO (monoamine oxidase) A and B has demonstrated unequivocally that these enzymes are made up of different polypeptides, and our understanding of MAO structure, regulation, and function has been significantly advanced by studies using their cDNA. MAO A and B genes are located on the X-chromosome (Xp11.23) and comprise 15 exons with identical intron-exon organization, which suggests that they are derived from the same ancestral gene. MAO A and B knock-out mice exhibit distinct differences in neurotransmitter metabolism and behavior. MAO A knock-out mice have elevated brain levels of serotonin, norephinephrine, and dopamine and manifest aggressive behavior similar to human males with a deletion of MAO A. In contrast, MAO B knock-out mice do not exhibit aggression and only levels of phenylethylamine are increased. Mice lacking MAO B are resistant to the Parkinsongenic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine. Both MAO A and B knock-out mice show increased reactivity to stress. These knock-out mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders.

/pdf/monoamine-oxidase-from-genes-to-behavior-48htyx6r2z.pdf

Monoamine oxidase: from genes to behavior.

Monoamine oxidases A and B (MAO-A and MAO-B) oxidatively deaminate neurotransmitter and xenobiotic amines. Since the cellular localization of the isoenzymes in the CNS and peripheral organs determines to a large extent which substrate has access to which isoenzyme, knowledge of their tissue distribution and cellular localization is essential. Here we describe how reversible and selective inhibitors of MAO-A and MAO-B [Ro 41-1049 and Ro 19-6327 (lazabemide), respectively] can be used, as tritiated radioligands, to map the distribution and abundance of the enzymes in microscopic regions of the rat CNS and peripheral organs, and human brain by quantitative enzyme radioautography. The in vitro binding characteristics of both radiolabeled inhibitors revealed them to be selective, high-affinity ligands for the respective enzymes. KD and Bmax values for 3H-Ro 41-1049 in rat cerebral cortex were 10.7 nM and 7.38 pmol/mg protein, respectively, and for 3H-Ro 19-6327 were 18.4 nM and 3.45 pmol/mg protein, respectively. In accordance with their potencies as enzyme inhibitors, binding to MAO-A and MAO-B was competitively inhibited by clorgyline (IC50 = 1.4 nM) and L-deprenyl (selegiline; IC50 = 8.0 nM), respectively. The capacities of various rat and human tissues to bind the radioligands correlated extremely well with their corresponding enzyme activities. As revealed by the respective binding assays, the distribution and abundance of MAO-A and MAO-B in the tissues investigated differed markedly. MAO-A was most abundant in the locus coeruleus, paraventricular thalamus, bed nucleus of the stria terminalis, median habenular nucleus, ventromedial hypothalamus, raphe nuclei, solitary tract nucleus, inferior olives, interpeduncular nucleus, claustrum, and numerous peripheral tissues, including liver, vas deferens, heart, superior cervical ganglion, and exocrine and endocrine pancreas. In contrast, MAO-B was most abundant in the ependyma, circumventricular organs, olfactory nerve layer, periventricular hypothalamus, cingulum, hippocampal formation, raphe nuclei, paraventricular thalamus, mammillary nuclei, cerebellar Bergmann glia cells, liver, posterior pituitary, renal tubules, and endocrine pancreas. The cellular localization of the isoenzymes in both rat and human brain differs markedly and does not reflect the distribution of the presumed natural substrates, for example, absence of MAO-A in serotoninergic neurons. Indeed, the present evidence suggests that, whereas MAO-A is found in noradrenergic and adrenergic neurons, MAO-B occurs in astrocytes, serotoninergic neurons, as well as ventricular cells, including most circumventricular organs. The physiological roles of the enzymes are discussed in the light of these findings, some of which were unexpected.(ABSTRACT TRUNCATED AT 400 WORDS)

https://www.jneurosci.org/content/jneuro/12/5/1977.full.pdf

Quantitative enzyme radioautography with 3H-Ro 41-1049 and 3H-Ro 19-6327 in vitro: localization and abundance of MAO-A and MAO-B in rat CNS, peripheral organs, and human brain.

Biochemistry and genetics of monoamine oxidase.

Radical Ideas about Monoamine Oxidase

Molecular cloning of a cDNA for rat liver monoamine oxidase B.

The cDNA for rat monoamine oxidase A (MAO-A) mRNA was isolated from a liver cDNA library in λ gt11 as the cDNA species cross-hybridizing with rat monoamine oxidase B (MAO-B) cDNA. The primary structure of the protein, deduced from the nucleotide sequence, consisted of 526 amino acid residues and its molecular mass was calculated to be 59.6 kD. The amino acid sequence shows about 70% identity with that of rat MAO-B. Northern blot analysis showed that MAO-A mRNA was expressed in various rat tissues and the highest expression was observed in heart. The MAO-B mRNA was quite different from MAO-A mRNA in the tissue-specific expression and liver had the highest level of the mRNA.

Primary structure of rat monoamine oxidase A deduced from cDNA and its expression in rat tissues.

1. The sulfite oxidases from various vertebrates, including rat, rabbit, chicken, frog, and eel, were partially purified and their physiochemical, kinetic, and immunochemical properties compared. The physicochemical and kinetic properties of these five enzymes were similar. 2. Antibody against the molybdenum-containing peptide prepared from purified rat liver sulfite oxidase was raised in rabbits. In Ouchterlony double diffusion and quantitative immunoprecipitation tests, the antibody could form precipitates with the enzymes from rats and rabbits, but no reaction was observed with enzymes from other sources. 3. The sulfite-cytochrome c reductase activity of the enzymes from these five animals were inhibited by the antibody, though the enzymes from chicken, frog, and eel were less sensitive to the antibody than those from rat and rabbit. 4. The inhibition of binding between 3H-labeled rat sulfite oxidase and its antibody by unlabeled enzymes from other animals demonstrated that 10 to 20% of the antibody could cross-react with these enzymes.

Toyoko Kuwahara

Papers

Molecular cloning of a cDNA for rat liver monoamine oxidase B.

Primary structure of rat monoamine oxidase A deduced from cDNA and its expression in rat tissues.

Comparative Immunochemical Studies of Sulfite Oxidases of Vertebrate Livers