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Brain monoamine oxidase A activity predicts trait aggression.

ABSTRACT: The genetic deletion of monoamine oxidase A (MAO A), an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, Mendelian Inheritance in Men database number 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in vivo in healthy nonsmoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the multidimensional personality questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions, the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than one-third of the variability. Because trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression.

SUBMITTER: Alia-Klein N

PROVIDER: S-EPMC2430409 | biostudies-other | 2008 May

REPOSITORIES: biostudies-other

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Brain monoamine oxidase A activity predicts trait aggression.

Alia-Klein Nelly N Goldstein Rita Z RZ Kriplani Aarti A Logan Jean J Tomasi Dardo D Williams Benjamin B Telang Frank F Shumay Elena E Biegon Anat A Craig Ian W IW Henn Fritz F Wang Gene-Jack GJ Volkow Nora D ND Fowler Joanna S JS

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080501 19

The genetic deletion of monoamine oxidase A (MAO A), an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, Mendelian Inheritance in Men database number 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidenc ...[more]

PMID: 18463263

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Project description:Early theorists (Freud and Darwin) speculated that extremely shy children, or those with anxious temperament, were likely to have anxiety problems as adults. More recent studies demonstrate that these children have heightened responses to potentially threatening situations reacting with intense defensive responses that are characterized by behavioral inhibition (BI) (inhibited motor behavior and decreased vocalizations) and physiological arousal. Confirming the earlier impressions, data now demonstrate that children with this disposition are at increased risk to develop anxiety, depression, and comorbid substance abuse. Additional key features of anxious temperament are that it appears at a young age, it is a stable characteristic of individuals, and even in non-threatening environments it is associated with increased psychic anxiety and somatic tension. To understand the neural underpinnings of anxious temperament, we performed imaging studies with 18-fluoro-deoxyglucose (FDG) high-resolution Positron Emission Tomography (PET) in young rhesus monkeys. Rhesus monkeys were used because they provide a well validated model of anxious temperament for studies that cannot be performed in human children. Imaging the same animal in stressful and secure contexts, we examined the relation between regional metabolic brain activity and a trait-like measure of anxious temperament that encompasses measures of BI and pituitary-adrenal reactivity. Regardless of context, results demonstrated a trait-like pattern of brain activity (amygdala, bed nucleus of stria terminalis, hippocampus, and periaqueductal gray) that is predictive of individual phenotypic differences. Importantly, individuals with extreme anxious temperament also displayed increased activity of this circuit when assessed in the security of their home environment. These findings suggest that increased activity of this circuit early in life mediates the childhood temperamental risk to develop anxiety and depression. In addition, the findings provide an explanation for why individuals with anxious temperament have difficulty relaxing in environments that others perceive as non-stressful.

Project description:See Jellinger (doi:10.1093/awx190) for a scientific commentary on this article. The enzyme monoamine oxidases (B and A subtypes, encoded by MAOB and MAOA, respectively) are drug targets in the treatment of Parkinson's disease. Inhibitors of MAOB are used clinically in Parkinson's disease for symptomatic purposes whereas the potential disease-modifying effect of monoamine oxidase inhibitors is debated. As astroglial cells express high levels of MAOB, the enzyme has been proposed as a brain imaging marker of astrogliosis, a cellular process possibly involved in Parkinson's disease pathogenesis as elevation of MAOB in astrocytes might be harmful. Since brain monoamine oxidase status in Parkinson's disease is uncertain, our objective was to measure, by quantitative immunoblotting in autopsied brain homogenates, protein levels of both monoamine oxidases in three different degenerative parkinsonian disorders: Parkinson's disease (n = 11), multiple system atrophy (n = 11), and progressive supranuclear palsy (n = 16) and in matched controls (n = 16). We hypothesized that if MAOB is 'substantially' localized to astroglial cells, MAOB levels should be generally associated with standard astroglial protein measures (e.g. glial fibrillary acidic protein). MAOB levels were increased in degenerating putamen (+83%) and substantia nigra (+10%, non-significant) in multiple system atrophy; in caudate (+26%), putamen (+27%), frontal cortex (+31%) and substantia nigra (+23%) of progressive supranuclear palsy; and in frontal cortex (+33%), but not in substantia nigra of Parkinson's disease, a region we previously reported no increase in astrocyte protein markers. Although the magnitude of MAOB increase was less than those of standard astrocytic markers, significant positive correlations were observed amongst the astrocyte proteins and MAOB. Despite suggestions that MAOA (versus MAOB) is primarily responsible for metabolism of dopamine in dopamine neurons, there was no loss of the enzyme in the parkinsonian substantia nigra; instead, increased nigral levels of a MAOA fragment and 'turnover' of the enzyme were observed in the conditions. Our findings provide support that MAOB might serve as a biochemical imaging marker, albeit not entirely specific, for astrocyte activation in human brain. The observation that MAOB protein concentration is generally increased in degenerating brain areas in multiple system atrophy (especially putamen) and in progressive supranuclear palsy, but not in the nigra in Parkinson's disease, also distinguishes astrocyte behaviour in Parkinson's disease from that in the two 'Parkinson-plus' conditions. The question remains whether suppression of either MAOB in astrocytes or MAOA in dopamine neurons might influence progression of the parkinsonian disorders.

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Brain monoamine oxidase A activity predicts trait aggression.

Publications

Brain monoamine oxidase A activity predicts trait aggression.

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