Orexin (hypocretin) and addiction

Abstract

Although originally implicated in appetite and sleep/wakefulness, the hypothalamic orexin (hypocretin) system has now been demonstrably linked with motivated behavior. This highly plastic system responds to reward-associated environmental stimuli and becomes pathologically overactive in addicted states. Here, we provide a brief overview of the roles of the orexin system in reward-seeking and addiction, as well as potential therapeutic opportunities for substance use disorders based on normalizing orexin function.

Keywords: dopamine; hypothalamus; plasticity; reward; substance use disorder.

Figure 1.. An overview of the orexin (hypocretin) system and its receptors.

(A) Orexin-producing neurons in lateral hypothalamus (LH) mediate a wide range of physiological processes via their broad projections throughout the neuroaxis. Of note, orexins promote reward behavior by influencing key reward centers, including ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC). Orexins also regulate sleep/wake states via inputs to arousal centers, including tuberomammillary nucleus (TMN), dorsal raphe nucleus (DR), and locus coeruleus (LC). (B) Orexin-producing neurons in lateral hypothalamus produce orexins A and B, which are cleaved from the common precursor prepro-orexin. (C) In efferent brain regions, orexins A and B signal via two G-protein-coupled receptors, orexin receptor 1 (Ox1R) and 2 (Ox2R); orexin A binds Ox1R and Ox2R with equal affinity, whereas orexin B preferentially binds Ox2R [2]. In general, although not exclusively, orexins mediate reward behaviors via their actions at Ox1R. The arousal and wake-promoting effects of orexin are primarily achieved via actions at Ox2R, but also rely on signaling at Ox1R.

Figure 2.. An overview of orexin system plasticity in addicted states.

Orexin neurons are preferentially recruited by drug-associated stimuli and act to translate this information into motivated behavior via outputs to reward centers, including the ventral tegmental area (VTA). (A) Hyperexcitability of this circuit reflects plasticity that occurs with repeated drug-cue pairings, whereby enhanced glutamatergic release (orange) onto orexin neurons (blue) increases neuronal activity [5]. Combined with drug-induced increases in orexin peptide production [6,7], this increased activity promotes heightened downstream orexin release in the VTA. (B) In the VTA, orexin promotes enhanced glutamate release onto dopaminergic (purple) neurons, as well as postsynaptic increases in first N-methyl-d-aspartate receptors (NMDAR) and later α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) to facilitate exaggerated dopamine release [9]. The net result of this plasticity is enhanced activity of the circuit in response to future presentations of drug-associated stimuli, resulting in the expression of hypermotivated, drug-seeking behaviors.