Alertness and feeding behaviors in ADHD: does the hypocretin/orexin system play a role?

Increasing evidence has suggested that patients with attention-deficit/hyperactivity disorder (ADHD) may present with a deficit of alertness and sleep disturbances. Recent studies have also pointed out a previously underestimated association between ADHD and abnormal eating behaviors, including binge eating. Since sleep/alertness disturbances and eating disorders may significantly increase the functional impairment of ADHD, gaining insight into their pathophysiology as well as into their treatment is of relevance to provide a better clinical management of patients suffering from ADHD. The hypocretin/orexin system comprises two distinct peptides, located in the hypothalamus, which are involved in several homeostatic functions. In particular, it has been suggested that hypocretin/orexin neurons located in perifornical and dorsomedial hypothalamic nuclei increase arousal, whereas those located in the lateral hypothalamus are primarily implicated in reward processing, stimulating feeding and other reward seeking behaviors. Given the involvement of the hypocretin/orexin system in the control of alertness and reward seeking (including feeding), we hypothesize that hypocretin/orexin neurons located in perifornical and dorsomedial hypothalamic areas are hypoactivated, while those located in the lateral hypothalamus are overactivated in patients with ADHD. If confirmed by further neurophysiological, imaging, and genetics studies, our hypothesis may help us progress in the understanding of the complex pathophysiology of ADHD. This might set the basis for the study of novel molecules, acting on the hypocretin/orexin system, aimed at increasing wakefulness and reducing binge eating and other abnormal reward seeking behaviors in patients with ADHD. We also suggest future studies on the potential therapeutic role of other molecules which have a complex interplay with the hypocretin/orexin system, such as the histamine H(1) receptor agonists, the histamine H(3) receptor antagonists, and the neuropeptide Y receptor antagonists. All this body of research would provide a tremendous opportunity to improve the quality of life of patients with ADHD by means of pathophysiologically oriented treatment.