Catechol O-methyltransferase Val158Met Genotype and Neural Mechanisms Related to Affective Arousal and Regulation

Drabant, Emily M.; Hariri, Ahmad R.; Meyer‐Lindenberg, Andreas; Muñoz, Karen E.; Mattay, Venkata S.; Kolachana, Bhaskar; Egan, Michael; Weinberger, Daniel R.

doi:10.1001/archpsyc.63.12.1396

Cited by 351 publications

(337 citation statements)

References 93 publications

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“…64 It is noteworthy that the personality domains affected by MAOA genetic variation (Harm Avoidance, Reward Dependence) correspond, in the Cloninger hypothesis, 5 to those neurotransmitter systems (serotonin, norepinephrine) impacted by MAOA during neurodevelopment. 16 In addition, genetic variation in COMT, previously linked to functional coupling in another neural circuit and associated with TPQ Novelty Seeking, 65 was not linked to functional coupling in the circuit identified here. Taken together, these findings are consistent with Cloninger's predictions regarding the neurochemical underpinnings of TPQ traits: Harm Avoidance (serotonin), Novelty Seeking (dopamine) and Reward Dependence (norepinephrine).…”

Section: Discussionmentioning

confidence: 52%

Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality

Buckholtz¹,

Callicott²,

Kolachana³

et al. 2007

Mol Psychiatry

198

170

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Little is known about neural mechanisms underlying human personality and temperament, despite their considerable importance as highly heritable risk mediators for somatic and psychiatric disorders. To identify these circuits, we used a combined genetic and imaging approach focused on Monoamine Oxidase A (MAOA), encoding a key enzyme for monoamine metabolism previously associated with temperament and antisocial behavior. Male carriers of a low-expressing genetic variant exhibited dysregulated amygdala activation and increased functional coupling with ventromedial prefrontal cortex (vmPFC). Stronger coupling predicted increased harm avoidance and decreased reward dependence scores, suggesting that this circuitry mediates a part of the association of MAOA with these traits. We utilized path analysis to parse the effective connectivity within this system, and provide evidence that vmPFC regulates amygdala indirectly by influencing rostral cingulate cortex function. Our data implicate a neural circuit for variation in human personality under genetic control, provide an anatomically consistent mechanism for vmPFC-amygdala interactions underlying this variation, and suggest a role for vmPFC as a superordinate regulatory area for emotional arousal and social behavior.

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Section: Discussionmentioning

confidence: 52%

Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality

Buckholtz¹,

Callicott²,

Kolachana³

et al. 2007

Mol Psychiatry

198

170

View full text Add to dashboard Cite

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“…However, a putative effect of tolcapone on noradrenergic and/or dopaminergic neurotransmission within brainstem circuits mediating the startle reflex cannot easily explain the selective startle increase by the drug in the Met/Met group only. Startle reflex increases during negative mood (see Lang and Davis, 2006 for review), and Met homozygotes have reduced resilience against such negative mood states (Smolka et al, 2005;Drabant et al, 2006;Weiss et al, 2007). It is therefore possible that the startle increase by tolcapone in the Met/Met group is related to tolcapone-induced dysphoric mood in Met158 homozygotes.…”

Section: Discussionmentioning

confidence: 99%

Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

Giakoumaki

Roussos

Bitsios

2008

Neuropsychopharmacol

129

105

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Recent evidence suggests that prepulse inhibition (PPI) levels relate to executive function possibly by a prefrontal cortex (PFC) dopamine (DA) link. We explored the effects of enhanced PFC DA signaling by the nonstimulant catechol-O-methyltransferase (COMT) inhibitor tolcapone, on PPI and working memory of subjects homozygous for the Val (low PFC DA) and the Met (high PFC DA) alleles of the COMT Val158Met polymorphism. Twelve Val/Val and eleven Met/Met healthy male subjects entered the study. Tolcapone 200 mg was administered in two weekly sessions, according to a balanced, crossover, double-blind, placebo-controlled design. PPI was assessed with 5 dB and 15 dB above background prepulses, at 30-, 60-, and 120 ms prepulse-pulse intervals. Subjects also underwent the n-back and the letter-number sequencing (LNS) tasks. PPI was lower in the Val/Val compared to the Met/Met group in the placebo condition. Tolcapone increased PPI significantly in the Val/Val group and tended to have the opposite effect in the Met/Met group. Baseline startle was not affected by tolcapone in the Val/Val group but it was slightly increased in the Met/Met group. Tolcapone improved performance in the n-back and LNS tasks only in the Val/Val group. Enhancement of PFC DA signaling with tolcapone improves both PPI and working memory in a COMT Val158Met genotype-specific manner. These results suggest that early information processing and working memory may both depend on PFC DA signaling, and that they may both relate to PFC DA levels according to an inverted U-shaped curve function. Neuropsychopharmacology (2008) 33, 3058-3068; doi:10.1038/npp.2008 published online 4 June 2008 Keywords: prepulse inhibition; sensorimotor gating; prefrontal cortex; dopamine; cognition; working memory INTRODUCTIONThe enzyme catechol-O-methyltransferase (COMT) is the main catabolic pathway by which dopamine (DA) is removed from the cortical synaptic cleft in humans (Karoum et al, 1994). Indeed, COMT is found in high concentrations in the cortex relative to subcortical regions (Matsumoto et al, 2003) consistent with the absence of functional DA transporters in cortical areas such as the prefrontal cortex (PFC) and hippocampus (Mazei et al, 2002). The Val158Met polymorphism in the COMT gene leads to an amino-acid substitution (valine (Val) to methionine (Met)) and results in the Met/Met variant showing 40% less enzymatic activity than the Val/Val (Chen et al, 2004). There is now abundant evidence (reviewed in Harrison and Weinberger, 2005;Tunbridge et al, 2006) that Met158 allele loading is dose dependently associated with superior performance on a variety of cognitive tests assessing executive function, as well as prefrontal physiology as assessed by neuroimaging. The evidence suggests that PFC DA facilitates 'focusing and stabilizing' activity in PFC networks during executive cognition, ie enhances prefrontal physiologic 'efficiency' by reduction of prefrontal noise (Cools et al, 2002;Mattay et al, 2002Mattay et al, , 2003.Prepulse inhibition (PPI) is thought...

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“…Following the landmark study of Egan et al (2001), a range of studies have shown that the Val 158 Met allele has a small but significant impact on prefrontal cognitive performance and efficiency, with Met 158 -carrying individuals performing better and/or more efficiently than Val 158 -carrying individuals (Barnett et al, 2007b). Conversely, the Val 158 allele is associated with more 'flexible' cognitive responses (Bilder et al, 2004), especially during emotional processing (Smolka et al, 2005;Drabant et al, 2006). Apart from Val 158 Met, other common COMT SNPs are noncoding (synonymous, intronic, or in the promoter or 3 0 -untranslated regions).…”

Section: Catechol-o-methyltransferasementioning

confidence: 99%

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

Harrison

Tunbridge

2007

Neuropsychopharmacol

278

217

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Sex differences in the genetic epidemiology and clinical features of psychiatric disorders are well recognized, but the individual genes contributing to these effects have rarely been identified. Catechol-O-methyltransferase (COMT), which metabolizes catechol compounds, notably dopamine, is a leading candidate. COMT enzyme activity, and the neurochemistry and behavior of COMT null mice, are both markedly sexually dimorphic. Genetic associations between COMT and various psychiatric phenotypes frequently show differences between men and women. Many of these differences are unconfirmed or minor, but some appear to be of reasonable robustness and magnitude; eg the functional Val 158 Met polymorphism in COMT is associated with obsessive-compulsive disorder in men, with anxiety phenotypes in women, and has a greater impact on cognitive function in boys than girls. Sex-specific effects of COMT are usually attributed to transcriptional regulation by estrogens; however, additional mechanisms are likely to be at least as important. Here we review the evidence for a sexually dimorphic influence of COMT upon psychiatric phenotypes, and discuss its potential basis. We conclude that despite the evidence being incomplete, and lacking a unifying explanation, there are accumulating and in places compelling data showing that COMT differentially impacts on brain function and dysfunction in men and women. Since sex differences in the genetic architecture of quantitative traits are the rule not the exception, we anticipate that additional evidence will emerge for sexual dimorphisms, not only in COMT but also in many other autosomal genes.

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Catechol O-methyltransferase Val158Met Genotype and Neural Mechanisms Related to Affective Arousal and Regulation

Cited by 351 publications

References 93 publications

Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality

Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality

Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

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