Nitric Oxide Synthase Genotype Modulation of Impulsivity and Ventral Striatal Activity in Adult ADHD Patients and Healthy Comparison Subjects

Abstract

(5), as evidenced by steeper temporal discounting rates, altered decision making, and an aversion to delay of gratification in reward-related tests (6-9). Temporal discounting is the patient's preference to receive smaller rewards sooner rather than larger rewards later and is postulated to be an intermediate phenotype for impulsivity. Neuroimaging studies have shown engagement of alternative brain regions in decision making in ADHD patients (10). A prominent feature is hypoactivation of the ventral striatum, a brain area with an important role in reward processing (11,12), during reward anticipation (13,14). Ventral striatal activity is also associated with impulsivity, a hallmark of ADHD (12,13). Recently, the NOS1 gene was identified as a candidate gene for ADHD and other impulsivity disorders (15). A variant in this gene was also among the top findings of a genome-wide association study in ADHD (3). NOS1 encodes nitric oxide synthase 1. Nitric oxide, the product of this enzyme's activity, acts as the second messenger downstream of the N-methyl-d-aspartate receptor and interacts with both the dopaminergic and serotonergic systems in the human brain. Nitric oxide inhibits monoamine transporters, thereby modulating the dopamine and noradrenalin concentration in the extracellular space (16). In addi-(A m J P sy c h ia try 2 0 1 1 ; 1 6 8 :1 0 9 9 -1 1 0 6 ) N itric O x id e S y n th a se G e n o ty p e M o d u la tio n o f Im p u lsiv ity a n d Ve n tra l S tria ta l A c tiv ity in A d u lt A D H D P a tie n ts a n d H e a lth y C o m p a riso n S u b je c ts O b je c tiv e : Attention deficit hyperactivity disorder (AD HD ) is a highly heritable disorder. The NO S1 gene encoding nitric oxide synthase is a candidate gene for AD HD and has been previously linked w ith im pulsivity. In the present study, the authors investigated the effect of a functional variable num ber of tandem repeats (VNTR ) polym orphism in NO S1 (NO S1 exon 1f-VNTR ) on the processing of rew ards, one of the cognitive deficits in AD HD. M e th o d :A sam ple of 136 participants, consisting of 87 adult AD HD patients and 49 healthy com parison subjects, completed a rew ard-related im pulsivity task. A total of 104 participants also underw ent functional m agnetic resonance im aging during a rew ard anticipation task. The effect of the NO S1 exon 1f-VNTR genotype on rew ard-related im pulsivity and rew ard-related ventral striatal activity w as exam ined.R e s u lts : AD HD patients had higher impulsivity scores and low er ventral striatal activity than healthy com parison subjects. The association betw een the short allele and increased im pulsivity w as confirm ed. How ever, independent of disease status, hom ozygous carriers of the short allele of NO S1, the AD HD risk genotype, dem onstrated higher ventral striatal activity than carriers of the other NO S1 VNTR genotypes.C o n c lu s io n s : The authors suggest that the NO S1 genotype influences im pulsivity and its relation w ith AD HD is m ediated through effects on this behavioral tr...

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