Orexin/Hypocretin System: Role in Food and Drug Overconsumption

Abstract

The neuropeptide orexin/hypocretin (OX), while largely transcribed within the hypothalamus, is released throughout the brain to affect complex behaviors. Primarily through the hypothalamus itself, OX homeostatically regulates adaptive behaviors needed for survival, including food intake, sleep-wake regulation, mating, and maternal behavior. However, through extra-hypothalamic limbic brain regions, OX promotes seeking and intake of rewarding substances of abuse, like palatable food, alcohol, nicotine, and cocaine. This neuropeptide, in turn, is stimulated by the intake of or early life exposure to these substances, forming a non-homeostatic, positive feedback loop. The OX receptor involved in these behaviors, adaptive behavior or substance seeking and intake, is dependent on the particular brain region that contributes to them. Thus, we propose that, while the primary function of OX is to maintain arousal for the performance of adaptive behaviors, this neuropeptide system is readily coopted by rewarding substances that involve positive feedback, ultimately promoting their abuse.

Orexin/hypocretin and dysregulated eating: Promotion of foraging behavior

“…Since that time, now twenty years ago, hundreds of articles have followed up on this idea in numerous species, confirming the involvement of OX in normal eating and extending the findings to excessive intake of palatable foods (Barson and Leibowitz 2017). Simultaneously, researchers have identified an important role for OX in other behaviors such as the promotion of waking as well as drug seeking (Barson and Leibowitz 2017, Mahler et al 2014, Mieda 2017. With its varied behavioral effects, the precise underlying role of OX remains elusive.…”

“…In the very first papers describing its discovery, the neuropeptide, orexin/hypocretin (OX), was suggested to play a major role in food intake and energy homeostasis (de Lecea et al 1998, Sakurai et al 1998. Since that time, now twenty years ago, hundreds of articles have followed up on this idea in numerous species, confirming the involvement of OX in normal eating and extending the findings to excessive intake of palatable foods (Barson and Leibowitz 2017). Simultaneously, researchers have identified an important role for OX in other behaviors such as the promotion of waking as well as drug seeking (Barson and Leibowitz 2017, Mahler et al 2014, Mieda 2017.…”

“…As such, OX (primarily through the orexin 1 receptor (OX1R) in the limbic system) can promote binge-like intake of energy-dense food but, in contrast to its role in drug relapse, it appears to play a minimal role in reinstatement of seeking for food that may no longer be available. Indeed, with OX known to promote arousal as well as feeding, it is notable that both humans and animals, during conditions of food deprivation, show elevated levels of OX, along with progressively shorter episodes of sleep and increased locomotor activity (Almeneessier et al 2018, Barson and Leibowitz 2017, Lauer and Krieg 2004, Sakurai et al 1998. Thus OX, during periods of limited access to food, appears to stimulate seeking or working for food as a survival strategy.…”

Targeting the Orexin System for Prescription Opioid Use Disorder

“…Repeated OrxR inhibition may cause nonspecific side effects by influencing numerous neural pathways. Dysfunctions of the Orx system can cause narcolepsy [65][66][67], while pharmacological manipulations of the Orx system can have nonspecific side effects on food intake [68][69][70], inhibitory responses [71][72][73], and learning and memory [74][75][76]. Such untoward effects need to be considered when investigating the clinical potential of OrxR antagonist treatment.…”

More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder

“…Hypocretin signaling is necessary for the regulation of sleep cycles (Nishino et al, 2000;Thannickal et al, 2000) in addition to playing an important role in feeding (Haynes et al, 2000;Inutsuka et al, 2014) and mating (Muschamp et al, 2007) behaviors. Furthermore, hypocretin has also been implicated in behaviors of overconsumption, including substance use disorders (Barson and Leibowitz, 2017). For a current review on hypocretin receptors, please see Wang et al (2018).…”