Is fetal brain monoamine oxidase inhibition the missing link between maternal smoking and conduct disorders?

Abstract

Smoking is the leading cause of preventable illness in the world today. Prenatal cigarette smoke exposure (PCSE) is a particularly insidious form because so many of its associated health effects befall the unborn child and produce behavioural outcomes that manifest themselves only years later. Among these are the associations between PCSE and conduct disorders, which have been mostly ascribed to the deleterious effects of nicotine on the fetal brain. Here we hypothesize that inhibition of brain monoamine oxidase (MAO) during fetal brain development, secondary to maternal cigarette smoking and in addition to nicotine, is a likely contributor to this association. MAOs play a central role in monoaminergic balance in the brain, and their inhibition during fetal development - but not during adult life - is known to result in an aggressive phenotype in laboratory animals. This paper provides theoretical and experimental support for the notion that cigarette smoke-induced inhibition of MAO in the fetal brain, particularly when it occurs in combination with polymorphisms in the MAOA gene that lead to lower enzyme concentration in the brain, may result in brain morphologic and functional changes that enhance the risk of irritability, poor self-control and aggression in the offspring. It also encourages research to evaluate whether the interaction of smoking exposure during fetal development and MAOA genotype increases the risk for conduct disorder over that incurred by mere fetal exposure to tobacco smoke.

Keywords: conduct disorder; maternal-fetal exchange; monoamine oxidase; smoking.

Fig. 1: Top–down view of conduct disorders. (A) Conduct disorders according to DSM-IV criteria. Conduct disorders can be suspected when a child displays a repetitive and persistent pattern of serious aggressive or nonaggressive misbehaviours against people, animals or property that may be characterized as belligerent, destructive, threatening, physically cruel, deceitful, disobedient or dishonest. A diagnosis of conduct disorder can be established by the presence of 3 (or more) of the included criteria in the past 12 months, with at least 1 criterion present in the past 6 months and with the disturbance in behaviour causing clinically significant impairment in social, academic or occupational functioning. (B) Key brain structures in the circuitry that controls emotion: (i) OPFC in green and the VMPFC in red, (ii) DLPFC, (iii) amygdala and (iv) ACG. Each of these interconnected structures plays a role in different aspects of emotion regulation, and abnormalities in one or more of these regions or in the interconnections among them are associated with failures of emotion regulation and also increased propensity for impulsive aggression and violence. (Davidson RJ, Putnam KM, Larson CL. Dysfunction in the neural circuitry of emotion regulation–a possible prelude to violence. Science 2000;289:591-4. Reprinted with permission from AAAS.) (C) Schematic model of one way in which developmental 5-HT disturbances may affect the neural circuitry regulating emotion, largely based on some of the reported effects of 5-HT transporter polymorphisms on the electrophysiology of the circuit. (Hariri AR, Holmes A. Genetics of emotional regulation: the role of the serotonin transporter in neural function. Trends Cogn Sci 2006; 10: 182-91. ©2006, with permission from Elsevier.) 5-HT = serotonin; ACG = anterior cingulate gyrus; DLPFC = dorsolateral prefrontal cortex; OPFC = orbital prefrontal cortex; PFC = prefrontal cortex; VMPFC = ventromedial prefrontal cortex.

Fig. 2: The rise and fall of MAO. (Top panel) Time course of nicotinic receptors and MAO's expression is overlaid atop that of critical events in the determination of brain morphometry during (and after) human gestation. (From: Lenroot RK, Giedd JN. Brain development in children and adolescents: insights from anatomical magnetic resonance imaging. Neurosci Biobehav Rev 2006;30:718-29. ©2006, with permission from Elsevier.) (Bottom panel) Positron emission tomography images of the MAOA radiotracer [¹¹C] clorgyline, the trapping of which is a function of both the concentration of MAOA and blood flow, as acquired at equivalent planes in the brains of a nonsmoker (top row) and a smoker (bottom row). The colour scale represents MAOA concentration (values of λk₃ range from 0.4 [red] to 0 [black]). (From: Fowler JS, Volkow ND, Wang GJ, et al. Brain monoamine oxidase A inhibition in cigarette smokers. Proc Natl Acad Sci U S A 1996;93:14065-9. ©1996 With permission, National Academy of Sciences, USA.) MAO = monoamine oxidase.

Fig. 3: Magnetic resonance imaging data demonstrate limbic and paralimbic regional volume changes in subjects with the low-activity MAOA variant (n = 97). Plots represent the summed volumes of voxels in predefined regions of interest, normalized to volume measures relative to the high-activity MAOA group mean (100%). (A) Compared with high MAOA subjects, low MAOA subjects exhibit significant volume reductions in bilateral amygdala, supragenual anterior cingulate and subgenual anterior cingulate cortex. Male and female subjects were combined. (B) Male low MAOA subjects showed increased lateral orbitofrontal volume, bilaterally, relative to high MAOA subjects. (From: Meyer-Lindenberg A, Buckholtz JW, Kolachana B, et al. Neural mechanisms of genetic risk for impulsivity and violence in humans. Proc Natl Acad Sci U S A 2006;103:6269-74. ©2006 With permisssion National Academy of Sciences, USA.) MAOA-H = high expressing monoamine oxidase-A variant; SEM = standard error of the means.

Fig. 4: Hypothetical model of the cumulative effect of various risk factors for developing conduct disorder. Normal brain development (A arrow) relies, among other factors, on carefully balanced concentrations of monoamine neurotransmitters in time and space. Genotypes that reduce MAOA activity during fetal development (B arrow) apply downward pressure on this process, particularly in males, who have only 1 allele. The magnitude of this pressure can induce morphologic changes in limbic and cognitive areas (i.e., significant volume reductions in the cingulate gyrus and bilateral amygdala [blue areas] as well as volume increases in the lateral orbitofrontal cortex [red spots] only in males) that, by themselves, seem compatible with behavioural outcomes within the normal range. Prenatal exposure to gonadal sex steroids (C arrow) is a powerful driver of differential neural circuit formation in the developing brain and no doubt a contributor to the higher aggressive and impulsive tendencies normally observed in males. Because of the neurodevelopmental impact of stress mechanisms, adverse (stressful or traumatic) childhood environments (D arrow) can push vulnerable children over the threshold and significantly increase the chances for developing disruptive behaviours later in life, even though genotypic differences in MAO enzymes no longer translate into different levels of MAO expression in adults. Many investigators have suggested that the risk for conduct disorders could become exacerbated by intrauterine exposure to tobacco smoke (E arrow) because nicotine usurps receptors that are critical during normal brain development and because other components in tobacco smoke can affect the development of circuits involved in the control of emotions through further reductions in MAO activity in the fetus. For the sake of simplicity, the genetically (MAOA high) resilient brain represented at the top is largely unaffected by the various downward vectors, but in reality, many combinations of heavy exposure to adverse environmental conditions and different genetic vulnerabilities can similarly lead to pathological behavioural outcomes. MAOA = monoamine oxidase type A.