Orexin/hypocretin role in reward: implications for opioid and other addictions

Abstract

Addiction is a devastating disorder that affects 15.3 million people worldwide. While prevalent, few effective treatments exist. Orexin receptors have been proposed as a potential target for anti-craving medications. Orexins, also known as hypocretins, are neuropeptides produced in neurons of the lateral and dorsomedial hypothalamus and perifornical area, which project widely throughout the brain. The absence of orexins in rodents and humans leads to narcolepsy. However, orexins also have an established role in reward seeking. This review will discuss some of the original studies describing the roles of the orexins in reward seeking as well as specific works that were presented at the 2013 International Narcotics Research Conference. Orexin signalling can promote drug-induced plasticity of glutamatergic synapses onto dopamine neurons of the ventral tegmental area (VTA), a brain region implicated in motivated behaviour. Additional evidence suggests that orexin signalling can also promote drug seeking by initiating an endocannabinoid-mediated synaptic depression of GABAergic inputs to the VTA, and thereby disinhibiting dopaminergic neurons. Orexin neurons co-express the inhibitory opioid peptide dynorphin. It has been proposed that orexin in the VTA may not mediate reward per se, but rather occludes the 'anti-reward' effects of dynorphin. Finally, orexin signalling in the prefrontal cortex and the central amygdala is implicated in reinstatement of reward seeking. This review will highlight recent work describing the role of orexin signalling in cellular processes underlying addiction-related behaviours and propose novel hypotheses for the mechanisms by which orexin signalling may impart drug seeking. LINKED ARTICLESThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 AbbreviationsBOLD, blood oxygen level-dependent; CeA, central nucleus of the amygdala; CPP, conditioned place preference; CRF, corticotropin-releasing factor; DAGL, DAG lipase; DMH, dorsomedial nucleus of the hypothalamus; LH, lateral hypothalamus; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; PFA, perifornical area; VTA, ventral tegmental area IntroductionNeurons containing orexin, also known as hypocretin, are firmly established as regulators of reward seeking. Orexin-A and -B (hypocretin-1 and -2) are peptides produced in neurons residing in the lateral and dorsomedial hypothalamus and perifornical area Sakurai et al., 1998) that have widespread projections throughout the brain . Orexin containing neurons project from the lateral hypothalamus (LH) to many areas of the mesolimbic 'reward pathway' including the ventral tegmental area (VTA) and the nucleus accumbens (NAc) (Di Chiara and Imperato, 1985;Koob and Bloom, 1988;Wise and Rompre, 1989) and these neurons are primarily implicated in rewardseeking behaviour. Within the VTA, 20% of neuronal inputs originating in the LH show immunolabelling for orexin (...

Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy

“…Unmatched two-tailed t tests or ANOVAs were used as appropriate. The number of subjects was determined in each group, generating data according to the formula: n = (z score) 2 × SD × (1 − SD)/(margin of error) 2 with  set at 0.05 and power set at 80%.…”

“…Addicts are unable to overcome opiate addiction, even as they realize the destructive effect it is having on them and their families (1). Prior work suggests that hypocretin cell activity is linked to pleasure-mediated arousal and, hence, may play a role in perpetuating addiction (2)(3)(4).…”

Distribution of the orexin-1 receptor (OX1R) in the mouse forebrain and rostral brainstem: A characterisation of OX1R-eGFP mice

“…Orexin-expressing neurons have highly divergent projections throughout the entire neuraxis , supporting a role for orexin in regulating various physiological processes such as sleep/wakefulness, arousal, feeding behaviour, energy metabolism, hormone secretion and autonomic homeostasis (Sakurai et al, 1998;Sutcliffe and de Lecea, 2000;Siegel, 2004;Meister, 2007;Berthoud and Munzberg, 2011). Additionally, considerable evidence implicates the orexin system in reward processing and drug-seeking behaviour (Boutrel et al, 2005;Harris et al, 2005;Lawrence et al, 2006;Mahler et al, 2012;Baimel et al, 2015).…”

Orexin-A/Hypocretin-1 Mediates Cocaine-Seeking Behavior in the Posterior Paraventricular Nucleus of the Thalamus via Orexin/Hypocretin Receptor-2

“…It is known that the PVT receives abundant projections from the hypothalamus that contains numerous peptides, including orexin/hypocretin (Orx/Hcrt; Freedman and Cassell, 1994;Otake, 2005;Parsons et al, 2006;Baimel et al, 2015 ABBREVIATIONS: aPVT, anterior paraventricular nucleus of thalamus; Hcrt, hypocretin; LH, lateral hypothalamus; Orx, orexin; PVT, paraventricular nucleus of thalamus; pPVT, posterior paraventricular nucleus of thalamus; SB334867, N-(2-methyl-6-benzoxazolyl)-N 9-1,5-ne th-aphthyridin-4-yl…”