BETHESDA, MD. -- Specific mutations to single genes may help predispose some patients to abnormal behaviors, Dr. Daniel R. Weinberger said at a psychopharmacology update sponsored by the National Institute of Mental Health.
In imaging studies, seemingly insignificant polymorphisms in three well-studied genes have been observed to have a relatively large impact on information processing and emotional responses.
Several studies have focused on the effects of a single-base pair substitution in the gene that codes for catechol-O-methyl-transferase (COMT), which breaks down dopamine, said Dr. Weinberger, chief of the clinical brain disorders branch of the National Institute of Mental Health.
The mutation makes the COMT enzyme about one-fourth as active as the normal enzyme. With less COMT activity in the prefrontal cortex, dopamine stays in the synaptic cleft for longer periods--on the order of hundreds rather than tens of milliseconds. The prefrontal cortex has no synaptic dopamine transporters, allowing dopamine to exert its effects there for longer periods than in other regions of the brain.
"A little more dopamine in the prefrontal cortex allows you to handle info a little quicker, more efficient, and a little more effectively" Dr. Weinberger said.
In MRI studies that look at the efficiency of information processing during working memory, people with two mutant COMT alleles performed the best, and people with one mutant allele performed better than those without any mutant alleles. The COMT mutation accounted for approximately 4% of variation in human frontal lobe executive cognition.
"This is a tiny effect all by itself," he said. "Four percent is not going to determine who's the top of the class, but for one gene to explain 4% of a very highly evolved and unique human function is quite an interesting phenomenon."
Approximately 50% of people have at least one of the mutant alleles, and 15% have both, he said.
The presence of the COMT mutant alleles may explain why some people respond well to amphetamines while others have adverse brain responses. Models predict that as the cortical dopamine level and receptor activation rises, people with no mutant alleles will derive the most benefit from amphetamine and improve their working memory performance by the greatest amount. Peoples with one mutant allele derive less benefit from amphetamines but will improve their performance. On the other hand, amphetamines will not help or will even decrease the performance of people with both mutant alleles, who already perform at an optimum level, and put such individuals at an increased risk of having an adverse brain response to them. …