RESUMO
INTRODUCTION: The influence of genetics in attention deficit hyperactivity disorder (ADHD) is well confirmed. However, identification of the specific genes involved in the pathogenesis of the disorder has proved to be difficult. Some authors suggest that the statistical power of molecular genetic studies could improve by replacing the diagnosis of the disease on the basis of clinical phenotype by quantitative risk markers closer to underlying genetic pathophysiology and gene action. Such markers, generically called 'endophenotypes', have attracted considerable scientific interest. When searching for new endophenotypes, priority must be given to markers that are based or anchored in the actual neuro-cognitive etiological models for ADHD. AIM: To describe the principal concepts involved in current models of ADHD and to briefly discuss their implication for identification of endophenotypes in ADHD. DEVELOPMENT: Herein we discuss the evolution of causal models for ADHD, from simple core deficit models to complex multiple-pathways models. Additionally, we describe the thalamo-cortico-striatal circuits, which is the common anatomic substrate for all causal models for ADHD. CONCLUSION: Thalamo-cortico-striatal circuits are recognized as the anatomic and functional substrate for all causal neuro-cognitive models for ADHD. In this context, any electrophysiological, behavioral, neuro-humoral or anatomic marker related with functions commanded by such system (mainly executive functions and reward functions) could be a promising endophenotype for ADHD. Special interest must be taken in markers that potentially allow us to 'dissect' parallels etiological pathways, like electrophysiological parameters or functional neuroimages. Finally, the psychometric properties of potential endophenotypes must be adequate for a reliable, sensitive and specific quantification.