Overview

Monoamine oxidase or MAO, an enzyme that catalyzes the oxidation of monoamines, has been correlated with the regulation of various neurochemicals, such as norepinephrine, serotonin, and dopamine, which in turn, reflect behavior. A defect in the MAO-A gene, leading to a shorter version of the gene and less expression of the enzyme is linked to higher levels of norepinephrine and serotonin, since these monoamine neurotransmitters cannot be broken down at the post-synaptic cell. High levels of norepinephrine and serotonin, combined with maltreatment, lead to individuals with higher anxiety, agitation, aggression, and anti-social behavior. These behavioral disorders caused by the shorter MAO gene, also known as the ‘warrior gene’, have been associated with an increase in criminal behaviors in individuals³. Studies using animal models have shown a correlation between higher norepinephrine and serotonin levels and increased aggression when the MAO enzyme is inhibited¹. Other experiments held out on individuals with low activity of MAO-A enzymes showed that aggression increased more rapidly compared to control groups, but only with provocation³. Case studies have shown that the behavioral disorders brought on by the MAO defect are due to maltreatment². These studies demonstrate how the environment plays a role in shaping the consequences of MAO enzyme deficiency. Because aggression and criminal behavior are multi-dimensional, treating only the enzyme deficiency will not be a sufficient cure. Although medication exists in the form of MAO inhibiters, it is more suited for depression and mood disorders rather than behavioral disorders. Preventative measures against abusive parents or therapy afterward would be a better approach to aggressive MAO related behavior.


4.1 Genes to Behavior


A mutation in the promoter region of the MAO-A gene causes an abrupt stop codon to shorten the gene³. This shorter version of the MAO-A gene is often referred to as the 'warrior gene' due to its correlation with aggressive individuals³. This mutation leads to less production of MAO-A enzymes. MAO-A metabolizes serotonin, norepinephrine, epinephrine, melatonin, dopamine, tyramine and tryptamine¹⁴. Less MAO-A leads to less degradation of these monoamine neurotransmitters, which leaves them in excess in the brain. This is also associated with Brunner syndrome¹⁷. The excess of serotonin and norepinephrine lead to anti-social, aggressive behaviors. On top of behavioral problems, MAO deficiency is also associated with depression, bipolar disorder, schizophrenia, anxiety disorders, and Parkinson's disease.

4.1.1 Norepinephrine Effects on Behavior


external image Catecholamines_biosynthesis.svgNorepinephrine is a stress hormone that regulates the fight-or-flight response, increasing heart rate, constricting blood vessels, increasing blood pressure, triggering the release of glucose, and increasing oxygen and blood supply to organs and muscles¹⁵. It effects alertness, arousal, influences the reward system¹⁶. It also plays an important role in decision making. Studies show a correlation between individuals with a low-activity polymorphism in the MAO-A gene and failing to make beneficial decisions in an experimental game setup.

In the case of overdose or excess norepinephrine, symptoms include slow heart rate, severe headache, blurred vision, trouble concentrating, increased sensitivity to light, stabbing chest or back pain, pale skin, sweating, vomiting, and seizure¹⁶. Behavioral changes include fear, anxiety, aggression and paranoia¹⁶. The aggression induced by norepinephrine is sometimes referred to as predatory aggression, since it is aggression in response to a 'predator' or aggregator. These characteristics have been strongly correlated with individuals suffering from MAO-A deficiency. In addition to aggression, slow heart rate and skin conductance are associated with anti-social behavior¹¹.

4.1.2 Serotonin Effects on Behavior


Serotonin or 5-HT plays an important role in regulating social responses. It is released as a signal in response to positive events, such as the presence of food or a mate. Its role in gauging social situations is influenced by environmental factors. It plays a role in social rank, such as inhibiting the fleeing reaction in subordinate individuals, but enhancing it in socially dominant or isolated individuals¹⁸.

Symptoms of serotonin syndrome or high levels of serotonin in the brain include headache, agitation, hypomania, mental confusion, hallucinations, coma, shivering, sweating, hyperthermia, hypertension, tachycardia, nausea, diarrhea, myoclonus, hyperflexia and tremor¹⁶. Behavioral changes include impulsivity, anxiety, aggression, extreme emotional states, and poor social functioning.

4.2 Monoamine Oxidase and Criminal Behavior


The behavioral changes a monoamine oxidase deficiency causes, particularly aggression and anti-social behaviors are associated with criminal activity. There have been several experiments and case studies held out on how a defected MAO-A gene can lead to criminal behaviors. This argument was also used in court to lessen the sentence on a criminal with an MAO-A deficiency¹⁹. However, environmental factors, such as childhood neglect also show a strong correlation with criminal and anti-social behaviors. The debate of nature vs. nurture comes into play with MAO-A's role in shaping behavior. There are still criticisms regarding the significant MAO-A has on behavior.



4.2.1 Case Studies and Experiments


Olivier Cases performed a study on a line of transgenic mice which were had transgene integration causing a deletion in the gene encoding MAO-A. This provides an animal model of MAO-A deficiency. In pup brains, serotonin concentrations were increased up to ninefold and norepinephrine concentrations increased up to twofold. Pup behavior alterations included trembling, difficulty in righting and fearfulness. Enhanced aggression in males was observed¹.




Dermott.pngRose McDermott's study demonstrated that aggression occurs with greater intensity and frequency as provocation is experimentally manipulated upwards, especially among low activity of MAO-A subjects. Subjects with MAO-A deficiencies and control subjects without the deficiency were paid to punish those they believed had taken money from them in the experiment by administering varying amounts of unpleasantly hot (spicy) sauce. If there was little money taken, the control subjects were found to administer more hot sauce than subjects with the deficiency. If there was a lot of money taken (high threat), those with the deficiency administered more hot sauce than the control subjects³. This is an example of predatory aggression and how the environment interacts with genotype.

4.2.2 Environmental Factors


Environmental factors, such as abuse, neglect or malnutrition in childhood present strong correlations in antisocial behavior and criminal activity. In Deise Mendes' study, the main biological factors of aggression were found to be a genetic predisposition (low activity of the MAO-A gene and serotonin transporter gene, along with variations in dopamine receptor genes), exposure to toxic substances during intrauterine development, and malnutrition. The main environmental factors were child abuse, poverty, crime and antisocial behavior in childhood¹⁰. The most significant factor was childhood neglect. This study demonstrates how a harsh environment catalyses aggressive behavior in those with the genetic predisposition.

Andreis Reif performed a study on 184 adult males signed up for forensic assessment. Violent and non-violent groups were assigned to each individual. Regression was performed and the results revealed independent effects of childhood environment and MAO-A genotype. Harsh childhoods was strongly associated with violent behavior. Forty-five percent of violent individuals carried the defected MAO-A allele, whle only 30% of non-violent carried the defect. It was also found that harsh childhoods interacted with the MAO-A deficient gene only later on in life when aggressive violent behaviors occurred¹².

Furthermore, prefrontal structure and functional deficits have also been linked to aggressive, anti-social behavior. Adrian Raine argues that the high demands of social interactions and executive control in adolescence overloads the late developing prefrontal cortex. This leads to prefrontal dysfunction and a lack of inhibitory control over antisocial, aggressive behavior that is seen at this stage¹¹.

4.2.3 Criticisms


The main criticisms regarding the effects the MAO-A gene has on behavior are regarding the multi-dimensional aspect of behavior. Because behavior is controlled by many hormones and neurotransmitters, along with being affected by the structure of the brain and the environment, some argue that the MAO-A gene cannot be responsible alone for any significant behavioral changes.

4.3 Applications


A deficiency in MAO-A enzymes can range in its severity due to other contributing factors. It can cause behavioral or mood changes, such as anxiety disorder, depression, attention-deficit disorder, or anti-social personalities, all of which have been looked at for treatment. It can also cause physiological problems, such as hypotension¹⁶. Furthermore, it can lead to complex problems, such as violent and criminal behaviors. For the more complex problems, more complex solutions are needed.

4.3.1 Monoamine Oxidase Inhibitors


Monomine oxidase inhibitors are classified as anti-depressants and are most suitable for treating depression and other mood disorders rather than the behavioral or physiological problems associated with MAO-A deficiency. MAO-Inhibitors reduce activity of MAO-A, thereby increasing levels of serotonin, dopamine, and norepinephrine in depressed individuals²⁰. However, there is no medical treatment for MAO-A deficiency. In Cases' study, the MAO-A aggression was revered with serotonin synthesis inhibitor paraclorhophenylalanin that reduced the serotonin levels in the mice¹. The best counteractive measure to take now would be to reduce food intake of amine-containing foods¹³.

4.3.2 Therapy and Preventative Measures


Due to the strong correlation between high adversity childhoods and anti-social behavior, reducing the likelihood of a neglect and abuse in childhood is the best preventative measure. Preventative measures on substance abuse while pregnant and malnutrition are important in lessening the chances of developing serious behavioral problems for those predisposed to them. Currently, the only other treatment is therapy. Cognitive behavioral therapy (CBT) involves working on maladaptive routines and behaviors to improve social responses and interactions with others.



See Also


MAO in Depression
MAO and Schizophrenia
MAO and Parkinson's Disease
MAO in Bipolar Disorder


References


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