Attention Deficit Hyperactivity Disorder (ADHD) and 5-HT2C receptor: A slight increase in the transmission of Cys23 to ADHD cases

Abstract

Recent evidence suggests that interaction with and balancebetween serotonergicand dopaminergic neurotransmissionis important in the mediation of hyperactive behaviour.Animal model studies have ®rmly implicated the genes of theserotonergic system in predisposing to ADHD. Serotoninexerts its effects via a heterogenous family of receptors ofwhich there are at least 14 distinct subtypes.The non-speci®c serotonin receptor agonist (m-chlorophenylpiperazine)is known to suppress locomotion in normalmice. However, when administered to mice bearing amutated 5-HTR2C gene, it induces hyperactivity in theseanimals (Lora et al., 2000). This effect was blocked by pretreatmentwith 5HT1B receptor antagonist, indicating thatthe behavioural consequences of the mCPP-induced 5HT1Breceptor stimulation are unmasked in animals devoid of5HT2C receptor function. A Cysteine to Serine substitutionat amino acid 23 of the 5HT2C has been identi®ed whichmay in ̄uence the receptor folding thereby hindering the formation of a normal hydrophobic pocket and subsequentlythe binding of bulky ligands. In a family based associationstudy design, we analysed the Cys-Ser polymorphism at the5HT2C receptor gene in 60 Irish ADHD trios using transmissiondisequilibrium test (TDT). We observed a slightincrease in the transmission of the Cysteine allele to theaffected ADHD cases (Chi-square ˆ1.8, P ˆ 0.26). Thismay suggest the involvement of 5HT2C gene in predisposingto ADHD.