Hypocretin/Orexin Receptor Antagonism and the Promise of Anticravingmedications: Myth or Panacea?

Abstract

A general consensus acknowledges that drug consumption (including alcohol, tobacco and illicit drugs) constitutes the leading cause of preventable death worldwide. An even more pessimistic observation suggests that drug abuse is not only a major cause of mortality but also it significantly deteriorates the quality of life of individuals suffering from the long-term debilitating effect of the disease. Despite the large body of evidence delineating the cellular and molecular adaptations induced by chronic drug consumption, the brain mechanisms responsible for drug craving and relapse remain insufficiently understood, and even the most recent developments in the field have not brought significant improvement in the management of drug dependence. Here, we review recent evidence demonstrating an important role for the hypocretin (orexin) neuropeptide system in regulating drug reward, and notably in preventing drug relapse. We then propose to discuss why disrupting the hypocretin system may serve as an anticraving medication since during the transition to addiction, the hypocretin system, normally orchestrating the appropriate levels of alertness required for the execution of goal-oriented behaviors, may be compromised and contribute to the pathological state by eliciting compulsive drug craving. Finally, we question the undesirable effects associated with a pharmacologically impaired hypocretin system, which may limit the applicability of the anticipated anticraving action of such a medication.