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January 21, 2010

Environment, biology combined impact behavior, speaker says

To the age-old debate whether nature or nurture — or in more modern terms, biology or environment — is predominant in human destiny, add the hypothesis that behavior is influenced by a interactive combination of the two, according to a Pitt expert who studies behavioral antecedents of heart disease.manuck

“To psychologists, heart disease is endlessly fascinating because there are behavioral causes and biological causes,” said Stephen Manuck in a Jan. 12 lecture titled “Honor, Guile and the New Genetics of Pugnacious Behavior,” following his installation as Distinguished University Professor of Health Psychology and Behavioral Medicine.

For instance, among psychosocial risk factors for cardiovascular disease are hostility, anger, anxiety, psychological depression, stress, lack of social connection to others and socioeconomic disparity, Manuck said. Behavioral risk factors for heart disease include smoking, diet, alcohol use, sedentary lifestyle and sleep disturbance. Among many biological risk factors are circulatory malfunction, high blood pressure and metabolic abnormalities.

“A question that has interested us for some time is prompted by the fact that many of these risk factors commonly occur together. So smoking and depression, for example, are highly co-morbid, that is are seen in the same individual. Anger, anxiety, depression are all associated with abnormalities of the autonomic function,” Manuck pointed out.

“These observations prompted us to look for something that might account for the correlated nature of heart disease risk,” he said. “One candidate we considered was biological, occurring in the brain. That system consists of neurons that release the neuro-transmitter serotonin, which is noted for its ubiquity and for its role in brain circuitry for emotion, metabolism and cardiovascular regulation.”

To test the influence of serotonin, Manuck and his research team conducted a clinical trial in which they administered a drug that greatly increases the release of serotonin.

“The mission: to release the serotonin source and activate the serotonin receptors, of which there are many throughout the brain, and when [serotonin] occurs in the hypothalamus it stimulates the pituitary gland to release several hormones into circulation, one of which is prolactin. The relative rise in prolactin, which may be measured in a blood sample taken peripherally, is taken as an index of central brain serotonergic responsivity,” Manuck explained.

The research results showed that people differ appreciably in the magnitude of their prolactin response, that is, their serotonergic responsivity, and that those ranges remain stable in individuals over time, he said. The findings indicate that persons with low serotonergic activity may have a reduced capacity to restrain impulses, a factor that when joined with antagonistic motivation is expressed as anger, acts of aggression or antisocial behavior.

“All things being equal, people who showed a greater prolactin response than others by having neurons release more serotonin, or have adaptors that are more sensitive to activation by serotonin, were less likely to have co-morbid risk factors, including, on the behavioral side, anger, hostility, depression, likelihood of smoking cigarettes, leading a sedentary lifestyle and, on the biological side, increases in blood pressure, obesity, insulin resistant elevated glucose, triglycerides, low HDL cholesterol. And those same cardiovascular risks improve if we can increase serotonergic responsivity,” Manuck said.

In another research study Manuck narrowed the focus to causes of an aggressive disposition, which typically expresses much more often in males than females, in order to study the potential genetic influences at work.

“It was well-known in the psychiatric literature that people with psychopathology — pathology of antisocial, aggressive behavior — tend to exhibit low serotonergic activity in the central nervous system,” Manuck said. “The diagnostic tendencies include antisocial personality disorder, disregard for social norms and rights of others, physical aggression on self or others and, among personality-disorder patients, the inability to restrain impulses of rage and aggressive compensation.”

The study asked the question: How strongly does the variation in serotonin responsivity correlate to antagonistic behavior? “We focused on men and assessed each individual’s lifetime history of aggressive behavior, the fights, the tantrums, the anger-related activities, the destruction of property and the like,” he said. “We also excluded from the analysis anyone with a psychiatric history or a history of alcohol or substance abuse or dependence.”

Manuck and his team hypothesized that there was a combination of environmental exposures and genetic differences among these test subjects. “We know some of the environmental correlates that diminish serotonergic functions in mammals, such as adversity in early rearing and external deprivation and, particularly in humans, socioeconomic disadvantage,” he said. “With respect to genetic factors, we can think of a number of targets of potential genetic influence: for instance, the enzymes that synthesize serotonin, the receptors that are activated by serotonin, the mechanisms that are responsible for terminating neuro-transmission.”

But searching for genetic causes of behavior is a course fraught with pitfalls, partly due to what Manuck called “the inglorious history of genetic theory in thinking about behavior.”

In the early 20th century many American biologists and later some psychologists argued that complex behavioral traits are transmitted genetically in the same manner as Gregor Mendel’s newly re-discovered so-called principles of heredity, which were published in the 1860s, Manuck said.

The strongest proponent of this belief was Harvard professor and National Academy of Sciences member Charles Davenport, who advocated genetic alteration to “improve” people’s characteristics.

Far-flung examples of Davenport’s genetic-caused characteristics were the “wayward girl” gene and, for boys, the “nomadism” gene, Manuck said. “And, my favorite, thalassophilia — the love of the sea — which Davenport reasoned was a sex-linked characteristic that, like color blindness, was expressed preferentially in males. Why? Obviously, because all naval officers were male!”

Davenport’s theories might have been harmless, except that they successfully pushed public policy toward the macabre.

“In many states laws were enacted for compulsory sterilization for the socially inadequate, laws which were upheld by the Supreme Court in Buck v. Bell, [a decision in which] Oliver Wendell Holmes famously asserted that ‘Three generations of imbeciles are enough,’” Manuck said.

Eventually, those laws were discarded, even by former supporters, and related eugenics laws were invalidated as well, he added.

“But by then, speaking of genetics of behavior was so suspect that attention turned increasingly to exclusively environmental explanations of behavior and psychological development,” Manuck noted.

Returning to contemporary thinking, Manuck asked: “What are the genes that influence behavior? This is not as easy to answer as it may seem given all the knowledge and power in genetic technology to identify and measure gene variation. A lot of genes have been touted for a while to be the signature of this or that behavior or pathology only to be [discredited]. Genes interact with other genes and do so perhaps differently in a different environment. In fact, it has been suggested that single genes are so small and genetic influences so complex as to make the question intractable.”

But fear not, Manuck said. “In the mid-1990s, Dutch families were discovered where many of the men were given to violent outbursts, ranging from public temper tantrums to arson to rape to simple assault. Only males were affected, but sisters of affected males often gave birth to an affected son. There was discovered a sex-linked mutation on the X chromosome,” he said. “Importantly, the mutation was not found in unaffected males.”

The mutation appeared on the monoamine oxidase A (MAOA) gene, which “de-animates” serotonin. But in humans, this genetic fault is extremely rare — found only in the small Dutch sample population — and therefore cannot possibly explain aggressive behavior in the general population, he said.

“It turns out, however, that a common regulatory variation also exists in the MAOA gene, such that alleles of a particular repeating sequence of the gene’s promoter region modulate the transcriptional efficiency of the gene. The variation also is located on the X chromosome, so it is a potential marker for aggressive behavior in males,” Manuck said.

This finding suggested that the genetic association of the MAOA promoter with a quantitative trait — the aggressive behavioral phenotype — may be mediated, in part, by allele-specific variation in central serotonergic responsivity, he said.

“So, what is the role of the MAOA gene? What is it that it contributes to the aggressive genotype? Does it promote an aggressive motivation or, instead, does it somehow promote the expression of an antagonistic motivation that comes from somewhere else?” Manuck asked. “In other words, does it unleash the mad dog or is it the jaws of the unleashed mad dog?”

More research is needed to answer those questions, he said.

—Peter Hart