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A study of the associations between dimensions of the ADHD/DBD phenotype …

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- ADHD and Disruptive behavior scores – associations with MAO-A and 5-HTT genes and with platelet MAO-B activity in adolescents

Attention Deficit Hyperactivity Disorder (ADHD) and Disruptive Behavior Disorders (DBD), including Conduct Disorder (CD) and Oppositional Defiant Disorder (ODD), are common child and adolescent psychiatric diagnoses. They are disabling and associated with high costs, both for society and in terms of individual suffering. Research regarding these disorders in children and adolescents from the general population is important in order to identify risk factors related to the etiology and prognosis [1]. ADHD affects 3–10% of school aged children [2]. Although the etiology of ADHD is not fully understood, a strong genetic component in the pathogenesis of the disease with an estimated heritability of 60–80% has been reported [1,3]. Consensus estimates suggest that ODD affects 5–10% of children and that 1–5% meet the diagnostic criteria for CD [4]. ADHD is a disorder with two separate underlying symptom dimensions; a hyperactive-impulsive dimension, including excessive activity and impulsive responding, and an inattentive dimension, including difficulties in sustained attention, distractibility, disorganization and lack of task persistence. In the same way DBD includes two dimensions; CD, characterized by a variety of persistent antisocial behaviors including acts of aggression, destruction of property, deceitfulness, theft and violation of commonly adhered to social problems, and ODD, characterized by a sustained pattern of chronic argumentativeness and anger associated with compromised social relations with parents and peers [5].

The symptoms included in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), categorical diagnoses of ADHD and DBD can also be studied as dimensions and conceptualized as quantitative variations of behaviors that most individuals show to a greater or lesser degree. There is support for an internal validity of the inattention, hyperactivity/impulsivity, oppositional defiant, and conduct disorder dimensions respectively [6]. Dimensional measures could distinguish different levels within the disorder [7].

Molecular, genetic and pharmacological studies have indicated that the dopaminergic and serotonergic systems play important roles in the development of ADHD [8]. At present, polymorphisms in three dopaminergic loci stand out as the most frequently replicated molecular correlates of ADHD: DRD4, DRD5, and DAT [9,10]. With regard to the serotonergic system, there are recent studies reporting involvement of serotonin in the etiology of ADHD [11]. Serotonergic components are involved in several behavioral traits such as aggression and impulsiveness, which are frequently associated with ADHD [12,13]. Furthermore, Gainetdinov et al [14] found that when administering serotonergic drugs together with methylphenidate to mice lacking the dopamine transporter protein, hyperlocomotor activity was reduced due to increased serotonin levels. Serotonin and dopamine exert regulatory control over each other, suggesting that serotonin, in addition to dopamine, is likely to be linked to ADHD.

Platelet monoamine oxidase (MAO) activity is highly genetically regulated and has repeatedly been associated with temperament [15]. Low platelet MAO-B activity correlates with personality traits such as sensation seeking, impulsivity and monotony avoidance. Platelet MAO-B has also been associated with deviant behavior such as type II alcoholism, which is a risk factor in adult ADHD. MAO-B is considered to be a marker of serotonergic capacity [15] and low activity has previously been associated with ADHD [16]. Two key genes expressing proteins of major importance for serotonergic activity are the genes encoding the serotonin transporter (5-HTT) and the monoamine oxidase A (MAO-A) enzyme. Both of these genes have functional promoter polymorphisms that have been shown to be associated with behavior: the 5-HTT LPR and the MAO-A VNTR [17,18]. A hypothesis which currently gains increasing experimental support is that prenatal serotonin levels are of importance for the development of the central serotonergic system. This hypothesis is supported by molecular genetic [19], pharmacological [20] and brain imaging studies [21].

In the present study, we have tested the hypothesis that a selection of biological markers, related to central serotonergic functioning, are associated with dimensions of the ADHD and DBD phenotype. In a population-based series of adolescent boys and girls, we investigated platelet MAO-B activity and the candidate genes: MAO-A (VNTR) and 5-HTT (LPR).

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