Maladaptive Impulsivity Research Articles

From parents to children: associations of traffic risks with impulsivity, family relationships and serotonin transporter genotype.

Road traffic injuries are the leading cause of death for young adults, and parents play a major role in shaping their traffic behaviour. Higher impulsivity (predictor of higher traffic risk) has been shown to be dependent on family relations and the serotonin transporter gene promoter polymorphism (5-HTTLPR). The specific mechanisms for the inheritance of risky traffic behaviour from parents to children are not clear, and the genetic aspect has not been studied before. We used data of Estonian Children Personality Behaviour and Health Study subjects (n = 596, mean age = 25.2 ± 0.6) and their parents (mothers, n = 460, mean age = 52.1 ± 5.8; fathers, n = 339, mean age = 54.1 ± 6.5). Family relationships scale, traffic risk questionnaires and Adaptive and Maladaptive Impulsivity Scale were filled out. The increased risk-taking behaviour of parents and worse quality of family relationship were significant predictors of higher traffic risk among subjects. Family support and impulsivity of fathers significantly predicted the subjects' traffic risk score in interaction with 5-HTTLPR genotype: l'/l' homozygous subjects with adaptively impulsive fathers had higher traffic risk, whereas for s'-allele carrying subjects family support was more significant. Parental role modelling and family relationships are significant predictors of future traffic behaviour of the child. Whether the behavioural example of the father or the influence of family relationships is more important in predicting future risky traffic behaviour, depends on the 5-HTTLPR genotype of the child.

MAOA methylation is associated with impulsive and antisocial behaviour: dependence on allelic variation, family environment and diet.

Congenital absence of monoamine oxidase A (MAO-A) activity predisposes to antisocial impulsive behaviour, and the MAOA uVNTR low-expressing genotype (MAOA-L) together with childhood maltreatment is associated with similar phenotypes in males. A possible explanation of how family environment may lead to such behaviour involves DNA methylation. We have assessed MAOA methylation and impulsive/antisocial behaviour in 121 males from the Estonian Children Personality Behaviour and Health Study. Of the 12 CpG sites measured, methylation levels at the locus designated CpG3 were significantly lower in subjects with antisocial behaviour involving police contact. CpG3 methylation was lower in subjects with alcohol use disorder by age 25, but only in MAOA-H genotype. No correlation between MAOA CpG3 methylation levels and adaptive impulsivity was found at age 15, but in MAOA-L genotype a positive correlation appeared by age 18. By age 25, this positive correlation was no longer observed in subjects with better family relationships but had increased further with experience of adversity within the family. MAOA CpG3 methylation had different developmental dynamics in relation to maladaptive impulsivity. At age 18, a positive correlation was observed in MAOA-L genotype with inferior family relationships and a negative correlation was found in MAOA-H with superior home environment; both of these associations had disappeared by age 25. CpG3 methylation was associated with dietary intake of several micronutrients, most notable was a negative correlation with the intake of zinc, but also with calcium, potassium and vitamin E; a positive correlation was found with intake of phosphorus. In conclusion, MAOA CpG3 methylation is related to both maladaptive and adaptive impulsivity in adolescence in MAOA-L males from adverse home environment. By young adulthood, this relationship with maladaptive impulsivity had disappeared but with adaptive impulsivity strengthened. Thus, MAOA CpG3 methylation may serve as a marker for adaptive developmental neuroplasticity in MAOA-L genotype. The mechanisms involved may include dietary factors.

Association of Impulsivity With Food, Nutrients, and Fitness in a Longitudinal Birth Cohort Study.

Impulsivity is a psychiatric vulnerability factor strongly associated with substance abuse but also with unhealthy diet. Whether these associations extend to specific nutrients is largely unknown. Therefore, we investigated the longitudinal association between diet, cardiorespiratory fitness, and 2 impulsivity dimensions in a representative sample of south Estonian adolescents and young adults. Impulsivity and dietary intake were measured 3 times in 2 birth cohorts at regular intervals in individuals aged 15 to 33 years. The sample included 2 birth cohorts of the longitudinal Estonian Children Personality Behaviour and Health Study. The analytic sample size consisted of 2883 observations (56.4% females). The primary outcomes were adaptive and maladaptive impulsivity scores measured by an original 24-item Likert-type questionnaire. Impulsivity scores were predicted from the food diaries data converted into nutrient categories. A linear mixed-effects approach was used to model the time dependence between observations. Lower maladaptive impulsivity was associated with higher cardiorespiratory fitness (β = -.07; 95% CI = -0.12; -0.03). Higher maladaptive impulsivity was associated with lower dietary intake of zinc (β = -.10; -0.15; -0.06) and vegetables (β = -.04; -0.07; -0.01) and higher intake of sodium (β = .06; 0.02; 0.10). Vitamin B6 was positively associated with adaptive impulsivity (β = .04; 0.01; 0.07). Additionally, some of the adjusted models showed significant but weak associations with selenium, alcohol, fish, and cereal products. Food choice may affect the neurochemistry and therefore regulate the manifestations of impulsivity. We identified associations between several (micro)nutrients and maladaptive impulsivity.

Driving risks of young drivers with symptoms of attention deficit hyperactivity disorder: association with the dopamine transporter gene VNTR polymorphism

Background Road traffic injuries are a leading cause of death for young adults, and young drivers with higher expression of symptoms of attention deficit-hyperactivity disorder (ADHD) could pose an even greater risk in traffic. Dopaminergic dysfunction has been found to occur in ADHD, with the dopamine transporter (DAT) gene VNTR polymorphism (DAT1 VNTR; rs28363170) being one of the most consistent genetic markers. Thus, we aimed at clarifying how the ADHD symptoms and the DAT1 VNTR relate to risk-taking behaviour in traffic, impulsivity and driving anger in young drivers. Method We used data of two traffic behaviour study samples (n = 741, mean age = 23.3 ± 7.2 years; n = 995, mean age = 22.9 ± 8.1 years) and the Estonian Children Personality Behaviour and Health Study (ECPBHS; traffic behaviour data n = 1,016, mean age = 25.2 ± 2.1 years). ADHD symptoms were assessed by self-report with the Adult ADHD Self-Report Scale (ASRS v1.1) and impulsivity with the Adaptive and Maladaptive Impulsivity Scale. Traffic behavioural measures were either self-reported (Driver Behaviour Questionnaire, Driving Anger Scale) or obtained from databases (registered accidents and violations). Results Drivers with more self-reported ADHD symptoms also reported more risk-taking in traffic and had more of recorded traffic accidents and violations. DAT1 9 R carriers had a higher probability of high traffic risk behaviour only if they also had ADHD symptoms. Conclusion Higher level of ADHD symptoms is a significant risk factor in traffic, and carrying of the DAT1 9 R allele appears to aggravate these risks.

Risk-taking in traffic is associated with unhealthy lifestyle: Contribution of aggressiveness and the serotonin transporter genotype

ObjectivesRisk taking behaviour, including in traffic, is related to impulsivity and aggressiveness, and so is unhealthy lifestyle. The serotonin transporter gene promoter polymorphism (5-HTTLPR) has been associated with impulsivity, aggression, alcohol use, speed limit exceeding and traffic accidents. The aim of this study was to examine whether subjects with less healthy eating and exercise habits take more risks in traffic, and whether impulsivity, aggressiveness and the serotonin transporter genotype could mediate or moderate any such associations. MethodA sub-sample of the Estonian Psychobiological Study of Traffic Behaviour (EPSTB (n ​= ​817) with mean age (SD) ​= ​31.4 (10.0) years filled out lifestyle questionnaires. Impulsivity was measured by Adaptive and Maladaptive Impulsivity Scale and aggressiveness by Buss – Perry Aggression Questionnaire. Traffic violation data in the previous 5 years period were obtained from police database. ResultsSpeed limit exceeders had higher physical and verbal aggression, higher AUDIT scores, they reported more vigorous physical activity and drinking energy drinks more often. Path analysis showed that higher AUDIT scores were associated with speeding via higher physical aggression. 5-HTTLPR was not directly associated with speeding or driving while impaired by alcohol (DWI), but 5-HTTLPR s’-allele carriers had lower AUDIT scores if they were not junk food eaters and the other way around, while l’/l’ homozygosity was associated with DWI via higher AUDIT scores. ConclusionSignificant associations exist between risky traffic behaviour and aspects of lifestyle such as consumption of alcohol or junk food or energy drinks, as well as engagement in vigorous physical activity, while traits such as aggressiveness and the variation in the serotonergic system appear as mediating and moderating factors. Interventions preventing accidents should focus on wider array of behaviours and use personalized approach. Genetic variation should be investigated regarding associations with risk taking and health behaviour, and response to interventions.

Interactive effects of DRD2 rs6277 polymorphism, environment and sex on impulsivity in a population-representative study

Previous research has shown that dopaminergic dysregulation and early life stress interact to impact on aspects of impulse control. This study aimed to explore the potentially interactive effects of the rs6277 polymorphism of the dopamine D2 receptor gene (DRD2), stressful or supportive environment and sex on behavioural and self-reported measures of impulsivity, as well as alcohol use – a condition characterised by a deficit in impulse control. The sample consisted of the younger cohort (n = 583) of the longitudinal Estonian Children Personality, Behaviour and Health Study. The results showed that the CC homozygotes (suggested to have decreased striatal D2 receptor availability) who had experienced stressful life events (SLE) or maltreatment in the family prior to age 15 showed higher self-reported maladaptive impulsivity at age 15. The genotype-SLE interaction and further association with sex was also evident in the frequency of alcohol use at age 15. Lack of warmth in the family contributed to significantly higher levels of thoughtlessness and more frequent alcohol use in CC carriers at age 25, whereas family support was associated with lower thoughtlessness scores in CC males, which may suggest a protective effect of supportive family environment in this group. Together the findings suggest that DRD2 rs6277 polymorphism, in interaction with environmental factors experienced in childhood and youth may affect facets of impulsivity. Future work should aim to further clarify the sex and age-specific effects of stressful and supportive environment on the development of neuronal systems that are compromised in disorders characterised by deficits in impulse control.

Low cholesterol levels in children predict impulsivity in young adulthood.

Severe behavioural issues such as impulsive action and suicide have since long been associated with low levels of cholesterol. While it is known that cholesterol plays a role in neural development and hence low levels of serum lipids could have long-term effects on behaviour, no longitudinal studies showed the association of serum lipids levels with impulsivity. We aimed to examine the prognostic properties of serum lipid levels during childhood and adolescence on measures of impulsivity during early adulthood in a representative birth cohort sample. We have investigated whether serum lipid levels measured at 9, 15, 18 and 25 years of age have an association with impulsivity in 25 years old young adults. This analysis was based on data of the birth cohort representative samples of the Estonian Children Personality Behaviour and Health Study (original n = 1238). Impulsivity was self-reported with the Adaptive and Maladaptive Impulsivity Scale. Total and low-density lipoprotein (LDL) cholesterol measured in boys aged 9, 15 and 18 years predicted disinhibition and thoughtlessness in 25-year-old young adults. High scores of disinhibition were associated with low total and LDL cholesterol levels in males but, while less consistently, with high total and LDL cholesterol levels in females. Cross-sectional analysis did not result in systematic outcomes. Serum lipid levels could have an impact on the development of Maladaptive Impulsivity starting from an early age. This effect of cholesterol continues throughout adolescence into young adulthood.

Relapse of drunk driving and association with traffic accidents, alcohol-related problems and biomarkers of impulsivity.

Individual biological predispositions should play a role in risky driving behaviour. Platelet monoamine oxidase (MAO) activity, dopamine transporter gene (DAT1) and neuropeptide S receptor 1 (NPSR1) gene polymorphisms have been identified as markers of impulsivity, alcohol use and excessive risk-taking. We aimed to find out how this knowledge on neurobiology of impulsivity applies to drunk driving and traffic behaviour in general. We have longitudinally examined the behaviour of drunk drivers (n = 203) and controls (n = 211) in traffic, in association with their alcohol-related problems, personality measures and the three biomarkers. We analysed differences between the subjects based on whether they had committed driving while impaired by alcohol (DWI) violation in a 10-year time period after recruitment or not and investigated further, what kind of predictive value do the different biomarkers have in committing DWI and other traffic violations and accidents. The original drunk drivers group had lower platelet MAO activity but further DWI was not significantly associated with this measure. Being a NPSR1 T-allele carrier contributed to the risk of repeatedly committing DWI. DAT1 9R carriers in contrast were involved in more traffic accidents by their own fault (active accidents), compared to 10R homozygotes in the whole sample. All groups with DWI also had significantly more alcohol-related problems and higher scores in maladaptive impulsivity compared to controls without DWI. Established biological markers of alcohol use and impulsivity can be reliably associated with everyday traffic behaviour and help in contributing to the understanding of the need for more personalized prevention activities.

Role of impulsivity and reward in the anti-obesity actions of 5-HT2C receptor agonists.

The selective 5-HT2C receptor agonist lorcaserin entered clinical obesity trials with the prevalent view that satiety was a primary mechanism of action. Subsequent Phase II and III trials demonstrated efficacy in terms of weight loss, although the overall effect size (~3% placebo-corrected change) is considered modest. Lorcaserin has been approved by the FDA for the treatment of obesity with lifestyle modification, but since its introduction in 2013 its sales are in decline, probably due to its overall modest effect. However, in some individuals, lorcaserin has a much more clinically significant effect (i.e. >10% placebo-corrected change), although what common features, if any, define these high responders is presently unknown. In the present article we highlight the evidence that alternative mechanisms to satiety may contribute to the anti-obesity effect of lorcaserin, namely effects on constructs of primary and conditioned reward and impulsivity. This may better inform the clinical evaluation of lorcaserin (and any future 5-HT2C receptor agonists) to subgroups of obese subjects characterized by overeating due to maladaptive impulsivity and reward mechanisms. One such population might be individuals diagnosed with binge eating disorder.

654. Investigation of Modulation of mGluR4 as a Novel Pharmacological Approach to the Treatment of Maladaptive Impulsivity

654. Investigation of Modulation of mGluR4 as a Novel Pharmacological Approach to the Treatment of Maladaptive Impulsivity

Nice guys: Homozygocity for the TPH2 -703G/T (rs4570625) minor allele promotes low aggressiveness and low anxiety

BackgroundTryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. We examined whether the TPH2 polymorphism -703G/T (rs4570625) is associated with aggressiveness and impulsivity, and the prevalence of psychiatric disorders, in a population-representative sample. MethodsWe used self and proxy reports on aggressive behaviour in the younger birth cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study collected at age 25, and earlier collected impulsivity and related data of both ECPBHS cohorts. ResultsThe TT homozygous males reported less aggressive behaviour in the Life History of Aggression interview at age 25. They also had significantly lower scores in Illinois Bully Scale peer reports, and less ADHD symptoms rated by teachers both at ages 9 and 15. The TT homozygotes of both sexes had the lowest Maladaptive Impulsivity at ages 18 and 25, and the highest Adaptive Impulsivity at age 25. The TT homozygotes also had low depressiveness and trait anxiety by age 25, and the odds ratio for the prevalence of anxiety disorders was 9.38 for the G-allele carriers. LimitationsThe main limitation of the study is the naturally occurring low number of subjects with the TT genotype. ConclusionsSubjects with the TPH2 rs4570625 TT genotype, especially males, exhibit less aggression and a favourable impulsivity profile, and develop anxiety disorders by young adulthood less often.

Effect of a human serotonin 5-HT2A receptor gene polymorphism on impulsivity: Dependence on cholesterol levels

BackgroundImpulsivity is multidimensional: Low impulse control may result in behavioural disorders, but acting on the spur of moment may also be advantageous. Previous studies have shown negative associations between different facets of impulsivity and serotonergic function. Other investigations have found negative correlations between serum lipid levels and impulsivity. MethodsWe have investigated whether the functional polymorphism -1438A/G in the serotonin 5-HT2A receptor gene (HTR2A) is associated with impulsivity levels and whether there is any interaction with serum lipid levels. This analysis was based on data of the population-representative Estonian Children Personality Behaviour and Health Study at age 25. Impulsivity was self-reported with the Adaptive and Maladaptive Impulsivity Scale. ResultsSubjects with the A/A genotype of the HTR2A -1438A/G polymorphism had higher scores of Maladaptive impulsivity, but not Adaptive impulsivity. In females, high LDL and total cholesterol levels increased the genotype effect. In males, in the highest quartile of total or LDL cholesterol the genotype effect was altered, with G/G homozygotes having the highest Maladaptive impulsivity levels. LimitationsOnly one cohort of the European Youth Heart Study (EYHS) was used in the current study and impulsivity measures were self-reported. ConclusionsOur results do not support the notion that low cholesterol levels universally lead to higher impulsivity, but it was found that high total and LDL cholesterol levels moderate the effect of the HTR2A gene promoter polymorphism. This suggests that future studies on impulsivity need to consider the interaction of serotonergic measures with the whole range of cholesterol levels.

A Functional Vesicular Monoamine Transporter 1 (VMAT1) Gene Variant Is Associated with Affect and the Prevalence of Anxiety, Affective, and Alcohol Use Disorders in a Longitudinal Population-Representative Birth Cohort Study.

Background:Inter-individual differences in the monoaminergic systems have been shown to moderate the risk for a lifetime history of anxiety, affective, and alcohol use disorders. A common single nucleotide polymorphism in the vesicular monoamine transporter 1 gene (VMAT1 rs1390938 G/A; Thr136Ile) has been reported as functional in vitro and associated with bipolar disorder and anxiety. We aimed at assessing the association between the VMAT1 genotype, affect, and affect-related psychiatric disorders in a longitudinal population-representative study.Methods:We used the database of the Estonian Children Personality Behaviour and Health Study (beginning in 1998). Cohorts of initially 9- (recalled at ages 15 and 18 years, n=579) and 15- (recalled at ages 18 and 25 years; n=654) year-old children provided self-reports on impulsivity, anxiety, depressiveness, neuroticism, and alcohol use. In addition, psychiatric assessment based on DSM-IV was carried out in the older cohort at age 25 years.Results:Subjects homozygous for the less prevalent A (136Ile) allele reported lower maladaptive impulsivity, state and trait anxiety, depressiveness, and neuroticism and were less likely to have been diagnosed with an affective, anxiety, and/or alcohol use disorder by young adulthood. While in the younger cohort alcohol use started at younger age, this birth cohort effect was dependent on genotype: only G allele carriers and in particular the GG homozygotes started alcohol use earlier.Conclusions: VMAT1 rs1390938/Thr136Ile is associated with mood, personality, and alcohol use in the general population. Subjects homozygous for the “hyperfunction” allele (AA; Ile/Ile) appear to be more resilient to these disorders.

Further evidence for the association of the NPSR1 gene A/T polymorphism (Asn107Ile) with impulsivity and hyperactivity.

Administration of neuropeptide S (NPS) elicits anxiolysis, arousal and higher activity in rodents. In humans, the NPS receptor (NPSR1) gene rs324981 A/T (Asn(107)Ile) polymorphism is associated with fear responses and anxiety. We have recently revealed an association of NPSR1 with impulsivity-related traits and psychopathology. In the present study the association of the NPSR1 genotype with impulsivity and attention-deficit/hyperactivity disorder (ADHD)-related symptoms was re-examined in two independent non-clinical cohorts. We used self-reports of two population-derived samples of the Estonian Psychobiological Study of Traffic Behaviour (EPSTB): a community car driving sample (n=491, MAge=37) and a driving school student sample (n=773, MAge=24). Impulsivity was measured with the Adaptive and Maladaptive Impulsivity Scale (AMIS) in both samples, and with the Barratt Impulsivity Scale (BIS) in driving schools only. For the latter sample, also measurement of ADHD symptoms was carried out with the Adult ADHD Self-Report Scale (ASRS). NPSR1 T-allele carriers had higher scores of impulsivity, motor restlessness and total ADHD scores. The effect on impulsivity originated from male participants but for ADHD symptoms the association was independent of sex. Thus we have confirmed in two additional population-derived samples that the T-allele of the NPSR1 rs324981 polymorphism is associated with increased impulsivity and ADHD-related traits.

Epigenetic regulation of cortical serotonin (5-HT) 5-HT2A:5-HT2C receptor balance in maladaptive impulsivity

Epigenetic regulation of cortical serotonin (5-HT) 5-HT2A:5-HT2C receptor balance in maladaptive impulsivity

Association of a functional variant of the nitric oxide synthase 1 gene with personality, anxiety, and depressiveness

A functional promoter polymorphism of the nitric oxide synthase 1 gene first exon 1f variable number tandem repeat (NOS1 ex1f-VNTR) is associated with impulsivity and related psychopathology. Facets of impulsivity are strongly associated with personality traits; maladaptive impulsivity with neuroticism; and adaptive impulsivity with extraversion. Both high neuroticism and low extraversion predict anxiety and depressive symptoms. The aim of the present study was to evaluate the effect of the NOS1 ex1f-VNTR genotype and possible interaction with environmental factors on personality, anxiety, and depressiveness in a population-representative sample. Short allele carriers had higher neuroticism and anxiety than individuals with the long/long (l/l) genotype. Male short/short homozygotes also had higher extraversion. In the face of environmental adversity, females with a short allele had higher scores of neuroticism, anxiety, and depressiveness compared to the l/l genotype. Males were more sensitive to environmental conditions when they had the l/l genotype and low extraversion. In conclusion, the NOS1 ex1f-VNTR influences personality and emotional regulation dependent on gender and environment. Together with previous findings on the effect of the NOS1 genotype on impulse control, these data suggest that NOS1 should be considered another plasticity gene, because its variants are associated with different coping strategies.

The Relationship between Impulsive Choice and Impulsive Action: A Cross-Species Translational Study

Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.

Links between self‐reported and laboratory behavioral impulsivity

A major problem in the research considering impulsivity is the lack of mutual understanding on how to measure and define impulsivity. Our study examined the relationship between self-reported impulsivity, behavioral excitatory and inhibitory processes and time perception. Impulsivity--fast, premature, thoughtless or disinhibited behavior--was assessed in 58 normal, healthy participants (30 men, mean age 21.9 years). Self-reported impulsivity as measured by Adaptive and Maladaptive Impulsivity Scale (AMIS) and behavioral excitatory and inhibitory processes as measured by Stop Signal Task were not directly related. Time perception, measured by the retrospective Time Estimation Task, was related to both. The length of the perceived time interval was positively correlated to AMIS Disinhibition subscale and negatively to several Stop Signal Task parameters. The longer subjects perceived the duration to last, the higher was their score on Disinhibition scale and the faster were their reactive responses in the Stop Signal Task. In summary our findings support the idea of cognitive tempo as a possible mechanism underlying impulsive behavior.

μ-Opioid receptors in the nucleus accumbens shell region mediate the effects of amphetamine on inhibitory control but not impulsive choice.

Acute challenges with psychostimulants such as amphetamine affect impulsive behavior in both animals and humans. With regard to amphetamine, it is important to unravel how this drug affects impulsivity since it is not only a widely abused recreational drug but also regularly prescribed to ameliorate maladaptive impulsivity. Therefore, we studied the effects of amphetamine in two rat models of impulsivity, the five-choice serial reaction time task and the delayed-reward task, providing measures of inhibitory control and impulsive choice, respectively. We focused on the role of opioid receptor activation in amphetamine-induced impulsivity as there is ample evidence indicating an important role for endogenous opioids in several behavioral and neurochemical effects of amphetamine. Results showed that amphetamine-induced inhibitory control deficits were dose-dependently attenuated by the preferential μ-opioid receptor antagonist naloxone, but not by the selective δ-opioid receptor antagonist naltrindole or κ-opioid receptor antagonist nor-BNI (nor-binaltorphimine dihydrochloride). In contrast, naloxone did not affect amphetamine-induced improvements in impulsive decision making. Naloxone also completely prevented inhibitory control deficits induced by GBR 12909 [1-(2-[bis(4-fluorophenyl)methoxy] ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride], a selective dopamine transporter inhibitor. Intracranial infusions of naloxone, the selective μ-opioid receptor antagonist CTAP (H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)), morphine, and the selective μ-opioid receptor agonist DAMGO ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin acetate salt) revealed that μ-opioid receptor activation in the shell rather than the core subregion of the nucleus accumbens (NAc) modulates inhibitory control and subserves the effect of amphetamine thereon. Together, these results indicate an important role for NAc shell μ-opioid receptors in the regulation of inhibitory control, probably via an interaction between these receptors and the mesolimbic dopamine system.

A functional NOS1 promoter polymorphism interacts with adverse environment on functional and dysfunctional impulsivity

Neuronal nitric oxide synthase (NOS1) knockout results in increased impulsive aggression in mice under adverse housing conditions. In line with this, we have previously shown that a functional promoter polymorphism of NOS1, termed NOS1 ex1f-VNTR, is associated with impulsivity-related traits and related disorders. This study aims to examine whether adverse environment interacts with the risk allele on impulsivity-related measures. We here studied a population-based cohort of Estonian pupils, recruited at the age of 9 years and followed up for another 9 years. For 435 subjects, measures on impulsivity (Adaptive and Maladaptive Impulsivity Scale, BIS-11, Stop Signal data, and Visual Comparison Test, VCT), environmental conditions (stressful life events and family environment), and NOS1 ex1f-VNTR genotype were available. We found a genotype main effect in that presence of a short NOS1 ex1f-VNTR allele was associated with higher levels of adaptive impulsivity, especially in males, but also worse performance in the VCT and the Stop Signal test. Both stressful life events as well as adverse family environment interacted with the risk genotype to increase maladaptive impulsivity. This study provides further evidence that short alleles of NOS1 ex1f-VNTR go along with impulsive behavior. In the absence of adverse environmental conditions, this may lead to a beneficial effect as functional forms of impulsivity are affected. This however is reversed under negative conditions, as dysfunctional impulsivity is increased under these circumstances. This data provides evidence that NOS1 ex1f-VNTR is subject to balancing selection potentially explaining persistence of the risk allele in the population.