The Serotonin Problem: Nasty Males from Nasty Females

[James Brody]

A fascinating paper by Meyer-Lindenberg and his team.

First, they distinguish pre and post natal development. One enzyme (monoamine oxidase A) may be "defective" prenatally and wash the new brain in lots of serotonin, NE, and dopamine. Monoamine oxidase B then takes charge.

Second, and be careful, this is my speculation: the new brain might experience withdrawal and acquire a bias towards narcissism, impulsiveness, and aggression, particularly in males who were given abusive treatment early in life!

Thus, a brain once rich in seroton, dopamine, and norepinephrine frequently becomes calmer and more cooperative when given medications that reinstate the former levels of serotonin, norepinephrine, and dopamine! (Omega-3s sometimes help...one more of many hints that link nutrition with irritability.)

Of course, aggressive hyperactive children will frequently elicit parental abuse. Feed and rear the little stinkers differently and different outcomes may follow. After all, one set of genes may contain switches for alternative developmental cascades. Such also lines up with the developmental careers of hyperactive rhesus males (Suomi) and with what happens in American ghettos and in a subset of Islamic schools. We are close to knowing so much but we do so little. We are roped to a track and see the train coming...

I've added emphasis to the following:

"Violent and criminal behavior are likely related to complex environmental and social circumstances, but heritable factors also have been implicated (1, 2). The specific neural mechanisms leading to delinquency and impulsive aggression are poorly understood, although they have been the subject of spirited speculation and debate for literally centuries (2– Arguably, the clearest link between genetic variation and aggression exists for monoamine oxidaseA(MAO-A, MIM 309850), a key enzyme in the catabolism of monoamines, especially serotonin. The serotonergic system has been implicated in impulsivity and manifest violent behavior in animals and both auto- and heteroaggression in humans (2).MAOA and -B genes, likely derived from the same ancestral gene, are both located on the X chromosome (Xp11.23), comprising 15 exons with identical intron– organization (5).MAO-A provides the major enzymatic clearing step for serotonin and norepinephrine during brain development, whereas MAO-B activity increases dramatically after birth (5). Mouse knockouts for MAOA, but not MAOB, have elevated brain levels of serotonin, norepinephrine, and dopamine. They show enhanced amygdala-dependent emotional, but not motor, learning (6), and males exhibit dramatically increased aggressive behavior (7). In humans, a Dutch kindred with a missense mutation in the MAOA gene has been described (8): hemizygous males, representing functional gene knockouts, exhibited a pattern of impulsively violent criminal behavior for generations. Although functionally disabling variants of the gene are rarities outside of the laboratory setting, a common variable number of tandem repeats polymorphism of the MAOA gene has been described that strongly impacts transcriptional efficiency: enzyme expression is relatively high for carriers of 3.5 or 4 repeats (MAOA-H) and lower for carriers of 2, 3, or 5 repeats (MAOA-L) (9). Although conflicting evidence exists for the association of genotype with trait impulsivity in human cross-sectional studies, a clear and pronounced gene-by-environment interaction was found in a large longitudinal study of children followed for 25 years in which MAOA-L predicted violent offenses in males with adverse early experience (maltreatment) [(10).

"Previous work has demonstrated a similar although less statistically robust and more focal effect on amygdala function as a consequence of genetic variation in the serotonin transporter, 5-HTTLPR, (17, 29); there, as here, it was the genetic variant associated with higher synaptic serotonin levels, presumably during neurodevelopment, that was associated with impaired limbic structure, increased amygdala activation, and relatively decreased response of cingulate circuitry regulating amygdala. The genetic data presented here, which show the opposite effects associated with the risk allele, suggest that these two dimensions may be genetically dissociable; argue against an association of MAOA genotype with instrumental aggression and for a genetic risk for impulsive violence; and indicate that, whereas both instrumental and impulsive aggression may be present to varying degrees in most violent offenders, the risk imparted by the specific genetic variation studied here contributes to the impulsive dimension of this complex behavior."

As for nasty females: MAO-A and B are X-linked! An irritable mother may well hide until she drops off a cascade of explosive sons!

JimB

Reference:

Meyer-Lindenberg AM, Buckholtz JW, Kolachana B, Hariri A, Pezawas L, Blasi, G, Wabnitz A, Honea R, Verchinski B, Callicott JH, Egan M, Mattay V, & Weinberger, DR (2006) Neural mechanisms of genetic risk for impulsivity and violence in humans. Proc. Nat Acad Sci. 103: 6269-6274.