Behavioral outcomes of monoamine oxidase deficiency: preclinical and clinical evidence

Abstract

Monoamine oxidase (MAO) isoenzymes A and B are mitochondrial-bound proteins, catalyzing the oxidative deamination of monoamine neurotransmitters as well as xenobiotic amines. Although they derive from a common ancestral progenitor gene, are located at X-chromosome and display 70% structural identity, their substrate preference, regional distribution, and physiological role are divergent. In fact, while MAO-A has high affinity for serotonin and norepinephrine, MAO-B primarily serves the catabolism of 2-phenylethylamine (PEA) and contributes to the degradation of other trace amines and dopamine. Convergent lines of preclinical and clinical evidence indicate that variations in MAO enzymatic activity—due to either genetic or environmental factors—can exert a profound influence on behavioral regulation and play a role in the pathophysiology of a large spectrum of mental and neurodegenerative disorders, ranging from antisocial personality disorder to Parkinson’s disease. Over the past few years, numerous advances have been made in our understanding of the phenotypical variations associated with genetic polymorphisms and mutations of the genes encoding for both isoenzymes. In particular, novel findings on the phenotypes of MAO-deficient mice are highlighting novel potential implications of both isoenzymes in a broad spectrum of mental disorders, ranging from autism and anxiety to impulse-control disorders and ADHD. These studies will lay the foundation for future research on the neurobiological and neurochemical bases of these pathological conditions, as well as the role of gene × environment interactions in the vulnerability to several mental disorders.

A mutation in the enzyme monoamine oxidase explains part of the Astyanax cavefish behavioural syndrome

“…The cavefish aminergic condition, including high neurotransmission indexes and a mutation in their MAO enzyme, would probably be considered strongly pathological in humans 61 , yet they thrive in their caves since about one million years. Fish were maintained at 23-26°C on 12:12-h light: dark cycle and they were fed twice a day with dry and living food.…”

Molecular aspects of monoamine oxidase B

“…Its inhibitors, used as antidepressant drugs for over 50 years, have been shown to raise brain amine levels. The observation that inhibition of MAO increases monoaminergic function has supported a long-running drug discovery effort to find novel drugs that inhibit MAO to treat mood and degenerative disorders, including depression, aggression, schizophrenia, hyperactivity, Parkinson's Disease (PD), and Alzheimer's Disease (AD) (Oreland, 2004, Murphy et al, 2006, Oreland et al, 2007, Fisar et al, 2010, Bortolato and Shih, 2011, Song et al, 2013.…”

“…The interest in drug design to increase monoamine levels is reflected in a constant stream of reviews. Several reviews in the last 5 years provide the wider background to MAO (Bortolato and Shih, 2011, Youdim and Reiderer, 2011, Ramsay, 2012, Song et al, 2013, Fowler et al, 2015 This review will include key references for the established facts but focus on examples of recent research on the expression, activity and inhibition of MAO B.…”

Greater Monoamine Oxidase A Binding in Alcohol Dependence

“…Unfortunately, these studies were inconclusive because none of them addressed several recently discovered biases that influence MAO-A levels, such as cigarette smoking (9,10), exposure to current or past major depressive episodes (11)(12)(13), and impulsive-aggressive personality traits (14,15). The latter covary with MAO-A levels, likely because of a neurodevelopmental influence of inherited MAO-A levels (16).…”