Monoamine Oxidase-A Genetic Variations Influence Brain Activity Associated with Inhibitory Control: New Insight into the Neural Correlates of Impulsivity Luca Passamonti, Francesco Fera, Angela Magariello, Antonio Cerasa, Maria Cecilia Gioia, Maria Muglia, Giuseppe Nicoletti, Olivier Gallo, Leandro Provinciali, and Aldo Quattrone Background: Previous evidence has shown that genetic variations in the serotonergic system contribute to individual differences in personality traits germane to impulse control. The monoamine oxidase-A (MAO-A) gene, coding for an enzyme primarily involved in serotonin and noradrenaline catabolism, presents a well-characterized functional polymorphism consisting of a variable number of tandem repeats in the promoter region, with high-activity and low-activity variants. High-activity allele carriers have higher enzyme expression, lower amine concentration, and present higher scores on behavioral measures of impulsivity than low-activity allele carriers. Methods: We studied the relationship of this polymorphism to brain activity elicited by a response inhibition task (Go/NoGo task), using blood oxygenation level– dependent (BOLD) functional magnetic resonance imaging in 24 healthy men. Results: Direct comparison between groups revealed a greater BOLD response in the right ventrolateral prefrontal cortex (Brodmann’s area [BA] 45/47) in high-activity allele carriers, whereas a greater response in the right superior parietal cortex (BA 7) and bilateral extrastriate cortex (BA 18) was found in low-activity allele carriers. Conclusions: These data suggest that a specific genetic variation involving serotonergic catabolism can modulate BOLD response associated with human impulsivity. Key Words: Impulsivity, MAO-A, gene polymorphism, prefrontal cortex, Go/NoGo task, BOLD-fMRI I mpulsivity is a personality trait characterized by response inhibition failure, reduced information processing, and intol- erance to the delay of reward, which has been associated with several psychiatric syndromes, such as borderline and antisocial personality disorders (Stein et al 1995). The loss of inhibitory mechanisms controlling for behavioral responses might result in an over-dependence on external stimuli to guide individual behavior and significantly impact suicidal, violent, and aggressive behavior (Plutchik and Van Praag 1995). Subtle dysfunctions of such inhibitory processes depend on both envi- ronmental and genetic variables and can determine differences in impulsive personalities (Seroczynski et al 1999). Studies conducted on subjects with violent/aggressive behav- ior related impulsivity to diminished levels of serotonin (5- hydroxytryptamine [5-HT]) (Coccaro 1989; King et al 2003; Lesch and Merschdorf 2000) and most likely to reduced 5-HT metabo- lites in cerebrospinal fluid (Roggenbach et al 2002); moreover, forebrain 5-HT depletion in rats has been associated with impulsive choices in several paradigms (Mobini et al 2000). Because the neurobiological dimension of impulsivity shows strong heritability, as demonstrated by twin studies (Coccaro et al 1993), it is conceivable that genetic variations in the serotonergic system (i.e., reuptake or catabolism) can significantly contribute to differences in subjects’ impulsivity. Although converging evidence has shown a strong relation- ship between impulsivity and genetic variations of the enzyme primarily responsible for 5-HT degradation, monoamine oxi- dase-A (MAO-A) (Caspi et al 2002; Foley et al 2004; Gade et al 1998; Manor et al 2002; Manuck et al 2000; Newman et al 2005), impulsive behavior has not been clearly associated with genetic variations in the promoter region of the gene coding for the 5-HT transporter. In particular, although a recent study (Courtet et al 2004) found that the frequency of a polymorphism of the 5-HT transporter gene (the “short” variant, which is associated with reduced efficiency of the 5-HT transporter function) is greater in impulsive subjects, several other studies failed to detect this association (Baca-Garcia et al 2004; Bayle et al 2003; Patkar et al 2002; Reist et al 2001). Catabolism of 5-HT is regulated by the activity of MAO, with the isoform MAO-A having much greater affinity for the substrate than the isoform MAO-B (Shih and Chen 1999). The MAO-A coding gene (Xp11.4-Xp11.3) presents a well- characterized polymorphism, consisting of a variable number of tandem repeats (VNTR) in the promoter region, with different length variants that selectively influence the protein transcription and hence the enzymatic activity (Denney et al 1999; Sabol et al 1998). Conflicting findings have been reported as to whether the low- or the high-activity allelic variant is the “risk” variant. The high-activity allele has been associated with low serotonergic responsivity, as assessed by fenfluramine challenge, and with impulsive personality traits in normal male subjects (Manuck et al 2000). Moreover, a significant association between the high- activity allele and behavioral measures of impulsivity has been demonstrated in patients with Tourette’s syndrome (Gade et al 1998), as well as in patients with attention-deficit/hyperactivity disorder (Manor et al 2002). Conversely, studies of maltreated children (Caspi et al 2002; Foley et al 2004) and of monkeys with reared experience (Newmann et al 2005) demonstrated a signif- From the Neurology Unit, Department of Neurosciences (LPa, LPr), Univer- sity “Politecnica delle Marche,” Ancona; Institute of Neurological Sci- ences (FF AM, AC, MCG, MM, GN, OG, AQ), National Research Council, Piano Lago di Magone, Cosenza; and Institute of Neurology (AQ), Uni- versity “Magna Graecia,” Catanzaro, Italy. Address reprint requests to Francesco Fera, M.D., National Research Council, Institute of Neurological Sciences CNR, Laboratory of Neuroimaging, Piano Lago di Mangone, Contrada Burga, Mangone (CS) 87050, Italy; E-mail: f.fera@isn.cnr.it Received February 1, 2005; revised June 7, 2005; accepted July 13, 2005. BIOL PSYCHIATRY 2006;59:334 –340 0006-3223/06/$32.00 doi:10.1016/j.biopsych.2005.07.027 © 2006 Society of Biological Psychiatry