The Orexin System in Addiction: Neuromodulatory Interactions and Therapeutic Potential

According to the World Drug Report, there are nearly 300 million drug users globally. Drug addiction is a chronic, relapsing brain disease that leads to medical, psychological, and social complications. This neuropsychiatric disorder is characterized by a compulsive drug-seeking behavior, continued use despite harmful consequence, and long-lasting changes in the brain. The reward system, which involves dopaminergic circuits, plays a key role in addiction. Dopamine levels have been described to fluctuate throughout the day, in a circadian fashion, and the effects of drugs have been shown to depend on the time when they are used. Hence, due to its important role in the control of circadian rhythms, the orexinergic system seems to have a role in the regulation of addiction. This system is composed by the orexin receptors 1 and 2 (OX₁R and OX₂R), the ligands orexin A (OXA) and orexin B (OXB) and their respective enzymes for degradation or synthesis. Here, we explore how orexin receptors and orexin peptides are involved in addiction. For instance, OX₁R has been shown to be strongly involved in specific behaviors such as drug-seeking for stimulants, alcohol and other addiction problems, whereas OX₂R appears to be linked with arousal and stress responses. We also investigate how the orexinergic system may regulate drug-seeking behavior by interaction with other brain systems such as the dopaminergic, cannabinoid or opioid systems. Finally, the potential of receptor complexes as new therapeutic targets to treat drug addiction is explored.