Attention-deficit hyperactivity disorder and the adrenergic receptors α1C and α2C

Abstract

Keywords: attention-deficit hyperactivity disorder; adrenergic receptor ␣1C; adrenergic receptor ␣2C; linkage; norepinephrineThe adrenergic system has been hypothesized to be involved in the etiology of attention-deficit hyperactivity disorder (ADHD) based on pharmacological interventions and animal models. Noradrenergic neurons are implicated in the modulation of vigilance, improvement of visual attention, initiation of adaptive response, learning and memory. In this study we tested the genes for two adrenergic receptors, ␣1C (ADRA1C) located on chromosome 8p11.2, and ␣2C (ADRA2C) located on chromosome 4p16, as genetic susceptibility factors in ADHD. For the adrenergic receptor ␣1C we used a C to T polymorphism that results in a change of Cys to Arg at codon 492 for the linkage study. For the adrenergic receptor ␣2C gene we examined a dinucleotide repeat polymorphism located approximately 6 kb from the gene. We examined these polymorphisms in a sample of 103 families ascertained through an ADHD proband. Using the transmission disequilibrium test, we did not observe biased transmission of any of the alleles of these polymorphisms. We conclude that the alleles at the polymorphisms tested in these two genes are not linked to the ADHD phenotype in this sample of families. Molecular Psychiatry (2001) 6, 334-337. While the recent investigation of the molecular genetics of ADHD has focused on the dopaminergic system, an extensive body of literature has implicated the involvement of the adrenergic system in ADHD. 1,2 The notion that the adrenergic system is involved in ADHD derives from several lines of research including the manipulation of the catecholamine system in animals and the pharmacological response to adrenergic agonists in humans. In rodents, norepinephrine depletion results in increased distractibility and motor hyperactivity and in non-human primates, stimulation of the noradrenergic system has been shown to improve cognitive function and distractibility. 3 The improvement in ADHD symptoms with tricyclic antidepressants has been attributed to the actions of these drugs in the reuptake of norepinephrine. 1 Noradrenergic receptors are divided into three major categories: alpha1, alpha2, and beta. Activation of alpha 1 receptors in rats promotes vigilance (sustained attention), decreases impulsivity, and influences working memory and behavioral activation while having only a minor role in the modulation of long-term memory. 4 The alpha adrenergic receptors have been classified as ␣1A, ␣1B, and ␣1D corresponding to their ligand binding properties. Four ␣ adrenoreceptors, ␣1a, ␣1b, ␣1c, and ␣1d, have been cloned 5 and the cloned ␣1c receptor 6 has been identified as the receptor corresponding to the alpha 1 A-ligand binding site. 5 The gene for the ␣1C receptor has been localized by somatic cell hybridization 7 and by multi-point linkage analysis to 8p11.2. 8 Thus far only a single polymorphism has been identified for this gene, a C to T change located in codon 492 resulting in a change of cysteine to argin...

Effects of Atomoxetine on Hyper-Locomotive Activity of the Prenatally Valproate-Exposed Rat Offspring

“…Used as an ADHD medication, ATX is a selective NE reuptake inhibitor in vitro and in vivo (Wong et al, 1982). Although there are a few experimental evidences suggesting the role of NET in the regulation of hyperactivity, conclusive evidence is sparse which directly connects NET in the regulation of hyperactivity in ADHD (Barr et al, 2001). Also, there are indirect pharmacological evidences suggesting the role of presynaptic α2 adrenergic receptor in the modulation of ADHD-like behaviors.…”

Candidate Gene Studies of Attention Deficit Hyperactivity Disorder

“…[66,67] 673 DEHB'de Aday Gen Çalışmaları www.cappsy.org Alfa 2C Noradrenerjik Reseptör Geni Alfa 2C reseptör geni kromozom 4p16 yerleşimlidir. [68] Coming ve arkadaş-ları eş zamanlı Tourette sendromu olan hastalarda alfa 2C reseptör geninde en çok çalışılan dinükleotit tekrar polimorfizmi ve DEHB belirtileri arasında ilişki bildirmişlerdir. [69] Ardından yapılan çalışmalarda alfa 2C reseptör geni ve DEHB arasında ilişkiye dair kanıt sağlanmamıştır.…”

“…[69] Ardından yapılan çalışmalarda alfa 2C reseptör geni ve DEHB arasında ilişkiye dair kanıt sağlanmamıştır. [68,70] Bu genin olası-lıkla DEHB fenotipine katkı sağladığı fakat major etkisi olan genlerden olmadığı düşünülmektedir.…”

“…Alfa 1 reseptöründe Cys 492Arg polimorfizmi (492.kodonda sistin /arjinin değişimini ile sonuçlan polimorfizm) araştırılmış fakat ilişki bulunamamış-tır. [68] Noradrenalin Taşıyıcısı Geni (NET)…”

O Processamento Seletivo Motor e o Deficit de Atenção em Escolares: Uma Abordagem Psicomotora

“…Associações dos genes que codificam os receptores α2A (ADRA2A) e α2C (ADRA2C) com escores elevados de TDAH em pacientes com síndrome de Tourette foram observadas por Comings et al 74 Entretanto, estes resultados não se repetiram em pacientes diagnosticados com TDAH, nem para o gene ADRA2A, 76 nem para o gene ADRA2C. 77 A investigação do gene do receptor adrenérgico α1C (ADRA1C) pelos mesmos autores também não evidenciou associação. Embora os polimorfismos analisados nos genes ADRA2A 74,76 e ADRA2C 74,77 sejam os mesmos, diferenças metodológicas em relação à caracterização clínica das amostras e procedimentos laboratoriais impedem comparações conclusivas entre os estudos.…”