Neurobiology of the Orexin System and Its Potential Role in the Regulation of Hedonic Tone

Orexin peptides comprise two neuropeptides, orexin A and orexin B, that bind two G-protein coupled receptors (GPCRs), orexin receptor 1 (OXR1) and orexin receptor 2 (OXR2). Although cell bodies that produce orexin peptides are localized in a small area comprising the lateral hypothalamus and adjacent regions, orexin-containing fibres project throughout the neuraxis. Although orexins were initially described as peptides that regulate feeding behaviour, research has shown that orexins are involved in diverse functions that range from the modulation of autonomic functions to higher cognitive functions, including reward-seeking, behaviour, attention, cognition, and mood. Furthermore, disruption in orexin signalling has been shown in mood disorders that are associated with low hedonic tone or anhedonia, including depression, anxiety, attention deficit hyperactivity disorder, and addiction. Notably, projections of orexin neurons overlap circuits involved in the modulation of hedonic tone. Evidence shows that orexins may potentiate hedonic behaviours by increasing the feeling of pleasure or reward to various signalling, whereas dysregulation of orexin signalling may underlie low hedonic tone or anhedonia. Further, orexin appears to play a key role in regulating behaviours in motivationally charged situations, such as food-seeking during hunger, or drug-seeking during withdrawal. Therefore, it would be expected that dysregulation of orexin expression or signalling is associated with changes in hedonic tone. Further studies investigating this association are warranted.