Catechol-O-methyltransferase genotype modulates opioid release in decision circuitry.

Impulsivity, a risk factor for substance abuse disorders, is modulated by the Val158 variant of the catechol-O-methyltransferase (COMT) gene. Rodent studies have shown that opioids enhance impulsivity. Furthermore, alcohol consumption leads to endogenous opioid release in the cortex and nucleus accumbens (NAc), and this opioid release is correlated with greater positive hedonic effect. Using the selective mu opioid receptor radioligand [¹¹C] carfentanil, we find that, following alcohol consumption, individuals with the COMT Val158 allele have greater opioid release in the right NAc but less release in medial orbital frontal cortex (OFC). These data suggest that genetic regulation of dopamine levels can affect alcohol consumption in part by modulating endogenous opioid release in specific brain regions implicated in reward, which in turn promotes impulsive choice.

Chronic dietary exposure to chlorpyrifos causes behavioral impairments, low activity of brain membrane-bound acetylcholinesterase, and increased brain acetylcholinesterase-R mRNA.

Chlorpyrifos (CPF) is an organophosphate (OP) insecticide that is metabolically activated to the highly toxic chlorpyrifos oxon. Dietary exposure is the main route of intoxication for non-occupational exposures. However, only limited behavioral effects of chronic dietary exposure have been investigated. Therefore, male Wistar rats were fed a dose of 5mg/kg/day of CPF for thirty-one weeks. Animals were evaluated in spatial learning and impulsivity tasks after 21 weeks of CPF dietary exposure and one week after exposure ended, respectively. In addition, the degree of inhibition of brain acetylcholinesterase (AChE) was evaluated for both the soluble and particulate forms of the enzyme, as well as AChE gene expression. Also, brain acylpeptide hydrolase (APH) was investigated as an alternative target for OP-mediated effects. All variables were evaluated at various time points in response to CPF diet and after exposure ended. Results from behavioral procedures suggest cognitive and emotional disorders. Moreover, low levels of activity representing membrane-bound oligomeric forms (tetramers) were also observed. In addition, increased brain AChE-R mRNA levels were detected after four weeks of CPF dietary exposure. However, no changes in levels of brain APH were observed among groups. In conclusion, our data point to a relationship between cognitive impairments and changes in AChE forms, specifically to a high inhibition of the particulate form and a modification of alternative splicing of mRNA during CPF dietary exposure.

Genetics of impulsive behaviour.

Impulsivity, defined as the tendency to act without foresight, comprises a multitude of constructs and is associated with a variety of psychiatric disorders. Dissecting different aspects of impulsive behaviour and relating these to specific neurobiological circuits would improve our understanding of the etiology of complex behaviours for which impulsivity is key, and advance genetic studies in this behavioural domain. In this review, we will discuss the heritability of some impulsivity constructs and their possible use as endophenotypes (heritable, disease-associated intermediate phenotypes). Several functional genetic variants associated with impulsive behaviour have been identified by the candidate gene approach and re-sequencing, and whole genome strategies can be implemented for discovery of novel rare and common alleles influencing impulsivity. Via deep sequencing an uncommon HTR2B stop codon, common in one population, was discovered, with implications for understanding impulsive behaviour in both humans and rodents and for future gene discovery.

The interaction between serotonin receptor 2A and catechol-O-methyltransferase gene polymorphisms is associated with the novelty-seeking subscale impulsiveness.

OBJECTIVE: Novelty seeking is a trait that has been consistently associated with problem behaviours. There is evidence for heritability of novelty seeking, but the molecular genetic basis of the trait is still widely unclear. METHODS: The interaction between polymorphisms of catechol-O-methyltransferase (COMT) and serotonin receptor 2A genes was examined in relation to novelty seeking and its different subscales in healthy Finnish adults. A subsample of 1214 participants derived from a population-based sample was genotyped for the COMT Val158Met (rs4680) and HTR2A T102C (rs6313) genes. Novelty seeking was measured twice, with a 4-year interval, using Cloninger's Temperament and Character Inventory. RESULTS: The interaction between COMT Val158Met and HTR2A T102C polymorphisms was found to be associated with subscale impulsiveness. T/T carriers of HTR2A T102C polymorphism, that also had Met/Met genotype of COMT Val158Met single nucleotide polymorphism, scored significantly higher on impulsiveness than Val allele carriers (P=0.005). CONCLUSION: Our results suggest that the interaction between dopaminergic and serotonergic genes might underlie impulsiveness. Together with earlier research our results also stress the importance of considering novelty seeking as a heterogeneous trait with its subscales having different genetic backgrounds.

MAOA alters the effects of heavy drinking and childhood physical abuse on risk for severe impulsive acts of violence among alcoholic violent offenders.

BACKGROUND: A polymorphism in the promoter region of the monoamine oxidase A gene (MAOA) has been shown to alter the effect of persistent drinking and childhood maltreatment on the risk for violent and antisocial behaviors. These findings indicate that MAOA could contribute to inter-individual differences in stress resiliency. METHODS: Recidivism in severe violent crimes was assessed after 8 years of nonincarcerated follow-up in a male sample of 174 impulsive Finnish alcoholic violent offenders, the majority of whom exhibited antisocial (ASPD) or borderline personality disorder (BPD) or both. We examined whether MAOA genotype alters the effects of heavy drinking and childhood physical abuse (CPA) on the risk for committing impulsive recidivistic violent crimes. RESULTS: Logistic regression analyses showed that both heavy drinking and CPA were significant independent predictors of recidivism in violent behavior (OR 5.2, p = 0.004 and OR 5.3, p = 0.003) among offenders having the high MAOA activity genotype (MAOA-H), but these predictors showed no effect among offenders carrying the low MAOA activity genotype (MAOA-L). CONCLUSION: Carriers of the MAOA-H allele have a high risk to commit severe recidivistic impulsive violent crimes after exposure to heavy drinking and CPA.

MAOA and the neurogenetic architecture of human aggression.

Antisocial aggression is a widespread and expensive social problem. Although aggressive behaviors and temperament are highly heritable, clinical and trait associations for the most promising candidate gene for aggression, MAOA, have been largely inconsistent. We suggest that limitations inherent to that approach might be overcome by using multimodal neuroimaging to characterize neural mechanisms of genetic risk. Herein, we detail functional, structural and connectivity findings implicating the low-expressing allele of the MAOA u-VNTR (MAOA-L) in adversely prejudicing information processing within a corticolimbic circuit composed of amygdala, rostral cingulate and medial prefrontal cortex. We propose that the MAOA-L, by causing an ontogenic excess of 5-hydroxytryptamine, labilizes critical neural circuitry for social evaluation and emotion regulation (the 'socioaffective scaffold'), thereby amplifying the effects of adverse early-life experience and creating deleterious sociocognitive biases. Our construct provides a neurobiologically consistent model for gene-environment interactions in impulsive aggression.

Platelet MAO activity and the 5-HTT gene promoter polymorphism are associated with impulsivity and cognitive style in visual information processing.

RATIONALE: Low capacity of the central serotonergic system has been associated with impulsive behaviour. Both low platelet monoamine oxidase (MAO) activity and the short (S) allele of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) are proposed to be markers of less efficient serotonergic functioning. OBJECTIVES: The effect of the two markers for serotonin system efficiency on performance in a visual comparison task (VCT) and self-reported impulsiveness (Barratt Impulsiveness Scale, BIS-11) were investigated in healthy adolescents participating in the Estonian Children Personality Behaviour and Health Study. Possible confounding effect of general cognitive abilities on the performance in VCT was controlled for. RESULTS: Low platelet MAO activity and carrying of the S allele of 5-HTTLPR were both associated with higher error-rate and more impulsive performance in VCT. Platelet MAO activity and 5-HTTLPR S allele had a significant interactive effect on self-reported impulsivity (BIS-11). The effect of platelet MAO activity on both self-reported and performance impulsivity was significant only in the S allele carriers. The effect of 5-HTTLPR S allele on impulsive performance remained significant after controlling for general cognitive abilities. CONCLUSIONS: The two markers of lower serotonergic capacity, 5-HTTLPR S allele and low platelet MAO activity, have a similar and partly synergistic influence on self-reported as well as performance measures of impulsivity.

Association of traffic behavior with personality and platelet monoamine oxidase activity in schoolchildren.

PURPOSE: Estimations, attitudes and behavioral decisions in everyday life, including traffic-related situations, are influenced by personality traits. It is known that that there is a strong link between certain personality traits, particularly impulsivity, and central serotonergic functioning. This study examined associations between traffic behavior, personality and platelet monoamine oxidase activity, a marker of central nervous system serotonergic neurotransmission, in schoolchildren. METHODS: Participants were 483 schoolchildren (aged 15.3 +/- .5 years) who filled in questionnaires on traffic behavior and personality. Platelet monoamine oxidase activity was measured radioenzymatically. RESULTS: Simple logistic regression analysis revealed that subjects with riskier traffic behavior had higher impulsivity (both adaptive as maladaptive facets) as well as lower Openness, Agreeableness, and Conscientiousness. In multiple logistic regression analysis, many of these associations became nonsignificant, but the high traffic risk group was more likely to have lower Agreeableness and lower platelet MAO activity. Low platelet MAO activity was a significant predictor of risky traffic behavior only in girls who were also influenced by higher Excitement Seeking. Smoking was an independent predictor of all groups with high traffic risks. CONCLUSION: Risky traffic behavior in schoolchildren is associated with basic personality dimensions, most consistently with Agreeableness, and with different aspects of impulsivity. Some of these traits, particularly in girls, may be related to central serotonergic neuronal activity.

A dimensional impulsive-aggressive phenotype is associated with the A218C polymorphism of the tryptophan hydroxylase gene: a pilot study in well-characterized impulsive inpatients.

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin, and association and linkage studies of its variants in suicidal and impulsive-aggressive behavior have brought conflicting results. This pilot study was designed to investigate whether TPH A218C genotypes could be associated with impulsive behavioral tendencies (IBTs) in consecutively admitted nonpsychotic nonorganic inpatients. Patients (20 females and 34 males; age, 38.8 +/- 11.8) did not differ from healthy nonimpulsive controls (16 females and 11 males; age, 35.2 +/- 10.2) regarding TPH genotypes, but in the patients, the number of IBT was related to the presence of the 218C allele. It was concluded that impulsive-aggressive behavior may be associated with the TPH genotype in well-characterized impulsive patients and that the present results stress the importance of considering impulsiveness-aggressiveness in studies investigating the relationship between suicidal behavior and TPH genotypes.

Tryptophan hydroxylase genotype is associated with impulsive-aggression measures: a preliminary study.

To assess the relationship between two phenotypes in an extremely well-characterized population of personality disorder patients-impulsive aggression and prolactin response to fenfluramine-and tryptophan hydroxylase (TPH) genotype, TPH genotype (at an intronic polymorphic site) and prolactin response to fenfluramine were assessed in 40 Caucasian patients with personality disorder. Impulsive aggression was assessed by using the Buss-Durkee Hostility Inventory (BDHI). Twenty-one male patients with the "LL" genotype had higher BDHI scores than men with the "UL" or the "UU" genotype. No relationship between genotype and prolactin response to fenfluramine was found. It was concluded that impulsive-aggressive behavior in male personality disorder patients may be associated with the TPH genotype.

Enzyme activity and behavior in hyperactive children grown up.

Thirty-one men, originally seen as children for problems with overactivity, distractibility, and impulsiveness, were reevaluated at ages 21-23 years. Subjects were interviewed and tested and provided a blood sample for analyses of dopamine-beta-hydroxylase (DBH), monoamine oxidase (MAO), and catechol-O-methyl-transferase (COMT). A series of Pearson correlations between the biological variables and psychological measures revealed that MAO levels were negatively associated with measures of drug involvement, cigarette use, fire-setting, and sensation seeking; DBH levels were positively associated with measures of sensation-seeking; and COMT levels were negatively associated with a measure of hostility and positively correlated with a measure of impulsiveness.

Neuropsychological correlates of platelet monoamine oxidase (MAO) activity in female and male subjects.

Platelet monoamine oxidase (MAO) activity has been found to have behavioral (psychiatric and personality) correlates and is assumed to be linked to central transmitter systems and thus presumably to neuropsychological processes. In the present study, computerized neuropsychological tests, a reaction time (RT) test and a visuo-spatial problem solving test, the Perceptual Maze Test (PMT), were given to 32 female and 29 male students, each sex group divided into three subgroups on the basis of platelet MAO activity. The tests yield measures of laterality (reaction time for left- versus right-sided stimuli) and different aspects of cognitive strategy and skill, e.g. time used for inspection of the maze, for processing the stimulus pattern, and for checking the correctness of solutions. Low MAO female subjects had shorter RTs, pronounced for left-sided stimuli, and shorter inspection times in the PMT compared to other female subjects. Low and high MAO males had difficulties in inhibiting responses, when required, and low MAO males were more rapidly prepared to respond to new stimuli after short intervals than other males. In the PMT, high MAO male subjects spent a smaller part of the total time on inspection in relation to other male groups and had more rubouts than low MAO males, whose maze solving behavior indicated higher visuo-spatial ability. The results are discussed in terms of possible neurochemical bases of impulsivity and psychopathy, and of spatial skill.