Role of orexin/hypocretin in reward-seeking and addiction: Implications for obesity

Abstract

Orexins (also named hypocretins) are recently discovered neuropeptides made exclusively in the hypothalamus. Recent studies have shown that orexin cells located specifically in lateral hypothalamus (LH) are involved in motivated behavior for drugs of abuse as well as natural rewards. Administration of orexin has been shown to stimulate food consumption, and orexin signaling in VTA has been implicated in intake of high-fat food. In self-administration studies, the orexin 1 receptor antagonist SB-334867 (SB) attenuated operant responding for high-fat pellets, sucrose pellets and ethanol, but not cocaine, demonstrating that signaling at orexin receptors is necessary for reinforcement of specific rewards. The orexin system is also implicated in associations between rewards and relevant stimuli. For example, Fos expression in LH orexin neurons varied in proportion to conditioned place preference (CPP) for food, morphine, or cocaine. This Fos expression was altered accordingly for CPP administered during protracted abstinence from morphine or cocaine, when preference for natural rewards was decreased and drug preference was increased. Additionally, orexin has been shown to be involved in reward–stimulus associations in the self-administration paradigm, where SB attenuated cue-induced reinstatement of extinguished sucrose- or cocaine-seeking. Although the specific circuitry mediating the effects of orexin on food reward remains unknown, VTA seems likely to be a critical target for at least some of these orexin actions. Thus, recent studies have established a role for orexin in reward-based feeding, and further investigation is warranted for determining whether function/dysfunction of the orexin system may contribute to the overeating associated with obesity.

The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.

Introduction

The neuropeptides orexin A and orexin B (also denoted hypocretin 1 and hypocretin 2) were discovered in the late nineties and are synthesized solely in hypothalamic neurons [1], [2]. Sakurai et al. characterized two individual receptors for the orexin system, termed OxR1 and OxR2 (also denoted HcrtR1 and HcrtR2) [2]. OxR1 binds both orexin A and orexin B but has a much lower affinity for orexin B, whereas OxR2 binds both peptides with a similar high affinity. Both receptors couple with G proteins; OxR1 couples exclusively with G_q subunits while OxR2 couples to both G_q and G_i/o[3]. Orexin neurons send dense fiber projections throughout the brain including cerebral cortex, hippocampus, thalamus, midbrain and spinal cord [4], [5]. Furthermore, OxR1 and OxR2 are widely distributed throughout the CNS but are largely non-overlapping and are regionally selective [6], [7], [8], [9].

Orexin has been implicated in feeding behavior, in keeping with the location of these cells in the area of lateral hypothalamus (LH) specifically associated with feeding. The initial study by Sakurai et al. [2] demonstrated that central administration of orexin A or orexin B into the lateral ventricle stimulated food consumption, which prompted them to name the new peptides “orexin”, meaning appetite [2]. Furthermore, this study showed that prepro-orexin mRNA is upregulated following fasting [2]. Subsequent studies confirmed that orexin A stimulated feeding, whereas systemic administration of the OxR1 antagonist SB-334867 (SB) reduced feeding [10], [11], [12], [13], [14], [15]. Importantly, it was shown that SB reduced feeding by selectively enhancing the behavioral satiety sequence rather than through aversive mechanisms [11], [12], [13], [14]. Other studies showed that the orexin neuronal field has reciprocal connections with areas known to regulate food intake including neuropeptide Y (NPY) neurons in arcuate nucleus [16], [17], and that orexin A-induced feeding is partially attenuated by antagonism of the NPY-Y1 receptor [18]. Furthermore, obese mice (ob/ob and db/db) show decreased prepro-orexin gene expression [19], and antagonism of OxR1 produced a greater reduction of high-fat intake in Osborne–Mendel rats, a rat strain susceptible to dietary-induced obesity, as compared to obesity-resistant rats [20]. Taken together, these findings led to the view that the orexin neuropeptides modulate a homeostatic central feedback mechanism regulating feeding.

Further interest in the orexin system was generated when concurrent studies implicated it in another homeostatic function, sleep–wakefulness. Two groups simultaneously reported that dysfunction in the orexin system was linked with narcoleptic symptoms in mice and dogs [21], [22]. Later work in humans showed that narcoleptics (with cataplexy) lack orexin in their CSF and lack most orexin neurons in posterior hypothalamus [23], [24], [25]. Together these findings led to the view that the orexin system is involved in arousal and maintenance of the waking state. In support of this view, additional findings showed that orexin neurons send dense projections to brain arousal areas including the locus coeruleus, tuberomammillary nucleus, and basal forebrain cholinergic system [4], [5], [26], [27] and that orexin application typically strongly activates these cells [17], [28], [29], [30]. Together, the findings that the orexin system is involved in both feeding and arousal led to the hypothesis that the primary function of this system was in promoting arousal in response to food deprivation and in a fashion to promote food consumption [1], [2]. Recent studies, however, have investigated a possible role for orexins in reward-seeking for food and drugs of abuse independently of deprivation. As discussed below, this reward-associated function of the orexin system may be separated from its role in homeostatic feeding and maintenance of the arousal state, and may be mediated by a separate population of (laterally located) orexin neurons.

Much attention has been focused recently on the role of orexin in drug reward (reviewed in [[30], [31], [32], [33]]); however, with the current growing obesity epidemic, several studies have now linked the orexin system to reward-based eating. Dysfunction of the orexin system may be a contributing factor in the overeating associated with obesity. This seems a plausible hypothesis given the fact that hypothalamus is optimally located within the brain to communicate with lower brainstem nuclei controlling homeostatic processes and higher cortical and limbic areas associated with motivation. Furthermore, there is overlapping neural circuitry involved in food and drug reward [34]. We recently reviewed orexin's role in drug addiction [30], [31]. Therefore, this review will focus on orexin's role in reward-based feeding and will only briefly highlight studies involving drug reward.