Molecules of Aggression

PET and SPECT have revealed abnormalities in dementia, movement disorders, depression, anxiety, and substance abuse. Molecular processes also are related to aggressiveness, emotional stability, conscientiousness, sociability, and selfishness.

Thoughts stimulated by controlled external events have been correlated with specific changes in molecular processes, such as F-18 FDG accumulation, in specific regions of the brain. Emotions, such as aggression, also can be correlated to chemical processes in different parts of the brain. Studies of aggressive behavior have focused on the DA, 5-HT, and NE systems, i.e., the monoamine systems.

An example is that from the BNL, led by Nellie Alia Klein and colleagues. PET studies were performed after the intravenous injection of the radioactive tracer C-11 clorgyline, which is bound by the monoamine oxidase (MAO) A enzyme (Figs. 6.6 and 6.7) in different parts of the brain.

The regional concentrations of MAOA in their brains were lowest in those men who were most aggressive. More aggressive men had lower C-11 clorgyline uptake; less aggressive

Fig. 6.6 (a) Section ofthe double helix ofthe gene expressing the enzyme MAOA. (b) C-11 corgyline PET scan showing the regional distribution in the brain of the MAOA enzyme. (c) Aggressive subject. (d) Aggressive behavior.

Fig. 6.7 Binding ofC-11 corgyiine inthe brain decreases with increas- 3 ing aggressiveness.

Aggression Trait

men had higher uptake. Of the 240 questions in the questionaire, only those questions related to short temper, vindictiveness, and enjoying violent movies were related to MAO A levels. There was no correlation between C-11 clorgyline regional uptake in the brain in those persons who were depressed or had other negative feelings. In essence, the MAOA activity in the brain of 27 healthy men was inversely promotional to how aggressive they were.

"The less MAOA the men had in their brain, the more they answered "yes" to statements about taking advantage of others, causing them discomfort . Our findings corroborate the relevance of brain MAOA in aggressive personality . If this model of understanding is tested on individuals who engage in violent behavior (such as domestic violence), it may show promise in the future for pharmacological intervention against violence" (Alia-Klein).

The radiotracer C-11 clorgyline binds to and is metabolized by the enzyme MAOA. Clorgyline blocks NE receptors in the brain that, in large doses, results in increased levels of NE in the cerebral cortex. There was no correlation between C-11 clorgyline uptake in the brain in persons who were depressed or had other emotions.

The enzyme MAOA is located in synapses of NE, 5-HT, and DA neurons, which are located in the locus ceruleus, placenta, intestine, and autonomic nervous system. MAOA breaks down 5-HT, NE and DA, rendering them inactive. Inhibition of MAOA activity helps alleviate depression because it slows the breakdown of epinephrine and NE.

The gene that expresses the MAOA enzyme is located on the X chromosome, and it is involved in the control of mood, aggression, and pleasure. Subjects with low MAOA activity react much more strongly to stress than those with high activity.

Ronald Bailey and colleagues at the University of Wisconsin (August 7, 2002) studied a cohort of 442 men from New Zealand whose lives had been followed from birth to age 26. Genotype analysis found 279 subjects had high MAOA activity and 163 had low MAOA activity. Subjects who suffered abuse as children and had low activity of the MAOA gene were nine times more likely to engage in antisocial behavior, such as persistent fighting, bullying, lying, stealing, or disobeying rules in adolescence. "As adults, 85% of the severely maltreated children who also had the gene for low MAOA activity developed antisocial outcomes, such as violent criminal behavior."

Caspi et al. (2002) also identified a relationship between MAOA and anti-social behavior. Males with the low enzyme-activity genotype were more likely to be convicted of a violent crime than maltreated males with a high-activity genotype.

One can use statistical methods, such as Bayes' theorem, to relate neurotransmitters to different types of behavior. It may someday be possible to predict future behavior by measuring regional molecular processes in the brain.

In persons suffering from substance abuse, Cornish and Kalivas of the Medical University of South Carolina found that cocaine blocks the reuptake of DA by presynaptic neurons in the nucleus accumbens, increasing DA levels in the synapse. The addict craves for the effects of DA on the brain.

Repeated exposure to cocaine increases the release of glutamate, the excitatory neu-rotransmitter. Glutamate receptors, such as NMDA, in postsynaptic neurons, are activated by glutamate. Each of the several types of glutamate receptors is transcribed by different genes and their mRNA.

In addition to being an excitatory neurotransmitter, glutamate is also a precursor in the synthesis of GABA, the most active inhibitory neurotransmitter in the human brain, illustrating the continual balancing of excitatory and inhibitory neuronal activity.

In summary, 5-HT, DA, endorphins, and estrogens are involved in the feelings of pleasure. Epinephrine, NE, and testosterone are involved in pain, depression, and anxiety. High serum testosterone levels are found in aggressive, decisive, tough-minded and competitive people. Men have good spatial perception skills, whereas women with high estrogen levels have good verbal skills.

5-HT-secreting neurons are located in high concentrations in the amygdala and hippocampus (Schroeder et al., 1991). 5-HT is released into the synapse from serotonergic presynaptic neurons, and it is bound to 5-HT receptors on postsynaptic neurons. The unbound 5-HT in the synaptic cleft is taken back up into the presynaptic neurons by so-called protein transporters on these neurons.

5-HT and other monoamines affect emotions, whereas ACh and DA affect movement and emotions. Blocking serotonin transporters on presynaptic neurons with drugs increases synaptic concentrations of 5-HT, which makes depressed patients feel better. Other neu-rotransmitters, such as endogenous opiates, increase pleasure and decrease pain.

UC raclopride and [123I]iodobenzamine are used to study D2 DA receptors; UC cocaine studies DA transporters. Transporters are often targets for treatment of psychiatric disorders, including depression and substance abuse.

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