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 cocaineseeking. 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 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.

Ghrelin directly targets the ventral tegmental area to increase food motivation

“…3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 19 While the importance of ghrelin in reward-motivated feeding is now strongly supported, and here we have indicated the VTA as a ghrelin-responsive neuroanatomical substrate underpinning motivated food reward behavior, it is possible that there are additional anatomical loci underlying these responses. In the arcuate nucleus ghrelin signaling stimulates the activity of NPY/AgRP neurons (Dickson et al, 1993, Kamegai et al, 2001) and, in lateral hypothalamus, the orexin neurons (Toshinai et al, 2003); orexin, NPY and AgRP have some role in reward behavior (Jewett et al, 1995, Tracy et al, 2008a, Cason et al, 2010 and therefore these cannot be excluded as an additional target site(s) of ghrelin that mediate some effects of ghrelin on the mesolimbic circuitry in addition to the direct effect of ghrelin on the mesolimbic circuit shown here.…”

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

“…Neuropeptides that are produced in the LH can modulate the activity of VTA-DA and striatal neurons. OX-containing neurons project from the LH to the VTA, where the OX 1 R plays a key role in regulating mesolimbic DA transmission and the rewarding properties of various drugs of abuse and food (Cason et al, 2010;Uramura et al, 2001;Zheng et al, 2007). Furthermore, BE episodes may be controlled through a specific influence on reward and reinforcement processes for HPF.…”

Effect of orexin-B-saporin-induced lesions of the lateral hypothalamus on performance on a progressive ratio schedule

“…It is possible that a more extensive depletion may be required in order to reveal an effect on the incentive value of food Another potentially important factor is the level of food deprivation. The subjects of this experiment were maintained at 80% of their free-feeding body weights, whereas most previous studies of the effect of manipulating orexinergic function on motivated behaviour have been carried out on non-deprived animals or under milder deprivation conditions than that used in this experiment Harris and Aston-Jones, 2006;Borgland et al, 2009;Cason et al, 2010;Sharf et al, 2010). It is not clear how this might have influenced the results, although the control of food intake is known to be different in nondeprived and deprived states (Rowland et al, 2001).…”