MAO-A appears at roughly 80% of adulthood levels at birth, increasing very slightly after the first 4 years of life, while MAO-B is almost non-detectable in the infant brain. Regional distribution of the monoamine oxidases is characterized by extremely high levels of both MAOs in the hypothalamus and hippocampal uncus, as well as a large amount of MAO-B with very little MAO-A in the striatum and globus pallidus. The cortex has relatively high levels of only MAO-A, with the exception of areas of the cingulate cortex, which contains a balance of both. Autopsied brains demonstrated the predicted increased concentration of MAO-A in regions dense in serotonergic neurotransmission, however MAO-B only correlated with norepinephrine.
Function
Monoamine oxidases catalyze the oxidative deamination of monoamines. Oxygen is used to remove an amine group from a molecule, resulting in the corresponding ketone and ammonia. Monoamine oxidases contain the covalently bound cofactorFAD and are, thus, classified as flavoproteins. Monoamine oxidase A and B share roughly 70% of their structure and both have substrate binding sites that are predominantly hydrophobic. Two tyrosine residues in the binding pocket that are commonly involved in inhibitor activity have been hypothesized to be relevant to orienting substrates, and mutations of these residues are relevant to mental health. Four main models have been proposed for the mechanism of electron transfer although there is insufficient evidence to support any of them.
They are well known enzymes in pharmacology, since they are the target for the action of a number of monoamine oxidase inhibitordrugs. MAO-A is particularly important in the catabolism of monoamines ingested in food. Both MAOs are also vital to the inactivation of monoamine neurotransmitters, for which they display different specificities.
Because of the vital role that MAOs play in the inactivation of neurotransmitters, MAO dysfunction is thought to be responsible for a number of psychiatric and neurological disorders. For example, unusually high or low levels of MAOs in the body have been associated with schizophrenia, depression, attention deficit disorder, substance abuse, migraines, and irregular sexual maturation. Monoamine oxidase inhibitors are one of the major classes of drug prescribed for the treatment of depression, although they are often last-line treatment due to risk of the drug's interaction with diet or other drugs. Excessive levels of catecholamines may lead to a hypertensive crisis, and excessive levels of serotonin may lead to serotonin syndrome. In fact, MAO-A inhibitors act as antidepressant and anti-anxiety agents, whereas MAO-B inhibitors are used alone or in combination to treat Alzheimer's disease and Parkinson's disease. Some research suggests that certain phenotypes of depression, such as those with anxiety, and "atypical" symptoms involving psychomotor retardation, weight gain and interpersonal sensitivity. However the findings related to this have not been consistent. MAOIs may be effective in treatment resistant depression, especially those that do not respond to tricyclic antidepressants. PET research shows that use of tobacco cigarettes heavily depletes MAO-B, mimicking the action of an MAO-B inhibitor. Smokers who smoke for emotional relief may therefore be unintentionally treating depression and/or anxiety that is better addressed by an MAO-B inhibitor.
Animal models
There are significant differences in MAO activity in different species. Dopamine is primarily deaminated by MAO-A in rats, but by MAO-B in vervet monkeys and humans. Mice unable to produce either MAO-A or MAO-B display autistic-like traits. These knockout mice display an increased response to stress.
Genetics
The genes encoding MAO-A and MAO-B are located side-by-side on the short arm of the X chromosome, and have about 70% sequence similarity. Rare mutations in the gene are associated with Brunner syndrome. A study based on the Dunedin cohort concluded that maltreated children with a low-activity polymorphism in the promoter region of the MAO-A gene were more likely to develop antisocial conduct disorders than maltreated children with the high-activity variant. Out of the 442 total males in the study, 37% had the low activity variant. Of the 13 maltreated males with low MAO-A activity, 11 had been assessed as exhibiting adolescent conduct disorder and 4 were convicted for violent offenses. The suggested mechanism for this effect is the decreased ability of those with low MAO-A activity to quickly degrade norepinephrine, the synaptic neurotransmitter involved in sympathetic arousal and rage. This is argued to provide direct support for the idea that genetic susceptibility to disease is not determined at birth, but varies with exposure to environmental influences. However, most individuals with conduct disorder or convictions did not have low activity of MAO-A; maltreatment was found to have caused stronger predisposition for antisocial behavior than differences in MAO-A activity. The claim that an interaction between low MAO-A activity and maltreatment would cause anti-social behavior has been criticized since the predisposition towards anti-social behavior could equally well have been caused by other genes inherited from abusive parents. A possible link between predisposition to novelty seeking and a genotype of the MAO-A gene has been found.
A particular variant, dubbed "warrior gene" in the popular press, was over-represented in Māori. This supported earlier studies finding different proportions of variants in different ethnic groups. This is the case for many genetic variants, with 33% White/Non-Hispanic, 61% Asian/Pacific Islanders having the low-activity MAO-A promoter variant.
Aging
Unlike many other enzymes, MAO-B activity is increased during aging in the brain of humans and other mammals. Increased MAO-B activity was also found in the pineal gland of aging rats. This may contribute to lowered levels of monoamines in aged brain and pineal gland.
