Role of orexin/hypocretin in dependence and addiction

Sharf, Ruth; Sarhan, Maysa; DiLeone, Ralph J.

doi:10.1016/j.brainres.2009.08.028

Cited by 95 publications

(69 citation statements)

References 81 publications

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“…6; one-way ANOVA: F 3,24 = 11.56, P < 0.01), suggesting that unopposed dynorphin actions within this brain area attenuate cocaine reward. These results appear to be at variance with those that have demonstrated the absence of intra-VTA SB334867 on cocaine self-administration in low-effort fixed ratio 1 (FR1) schedules of reinforcement (40). However, several reports have shown that as task demands increase, SB334867 is more effective in reducing drug taking (2,33).…”

Section: Orexin and Dynorphin Can Exert Balanced Opposing Effects Onmentioning

confidence: 49%

“…Further, the present experiments focus on the VTA and cannot rule out the possibility that the effects of orexin and dynorphin may not be dichotomous in other structures or that the VTA is the only structure in which orexin-dynorphin interactions influence behavior. For instance, there is evidence that orexin is involved in the stress response and may participate alongside dynorphin to engender negative affective states that accompany drug withdrawal (40,47). Clearly, additional work is necessary to determine the circumstances, anatomical loci, and mechanisms that appear to permit concerted vs. opposing actions of orexin and dynorphin in different behavioral paradigms.…”

Section: Discussionmentioning

confidence: 99%

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Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

Muschamp

Hollander

Thompson

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

216

213

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Hypocretin (orexin) and dynorphin are neuropeptides with opposing actions on motivated behavior. Orexin is implicated in states of arousal and reward, whereas dynorphin is implicated in depressive-like states. We show that, despite their opposing actions, these peptides are packaged in the same synaptic vesicles within the hypothalamus. Disruption of orexin function blunts the rewarding effects of lateral hypothalamic (LH) stimulation, eliminates cocaine-induced impulsivity, and reduces cocaine selfadministration. Concomitant disruption of dynorphin function reverses these behavioral changes. We also show that orexin and dynorphin have opposing actions on excitability of ventral tegmental area (VTA) dopamine neurons, a prominent target of orexin-containing neurons, and that intra-VTA orexin antagonism causes decreases in cocaine self-administration and LH self-stimulation that are reversed by dynorphin antagonism. Our findings identify a unique cellular process by which orexin can occlude the reward threshold-elevating effects of coreleased dynorphin and thereby act in a permissive fashion to facilitate reward.O rexin promotes arousal (1) and has been implicated in the rewarding effects of food (2, 3), sexual behavior (4), and drugs of abuse (5, 6). It is produced primarily within the hypothalamus (7), and acts at orexin 1 receptor (OX 1 R) and OX 2 R (also known as Hcrt-R1 and Hcrt-R2), which are expressed in many brain areas, including the ventral tegmental area (VTA) of the midbrain (8). Dynorphin, in contrast, is expressed widely, promotes depressive-like behaviors, and plays a key role in mediating the aversive effects of stress (9, 10). Activation of kappaopioid receptor (KORs), the receptors at which dynorphin acts (11), can attenuate the rewarding effects of drugs of abuse (12, 13) via actions that are mediated, at least in part, within midbrain dopamine (DA) systems (14, 15). Despite their seemingly opposing effects on motivation, there is evidence that these peptides may act in tandem; for example, both orexin and dynorphin are released during electrical stimulation of the hypothalamus (16). Like DA neurons, orexin and dynorphin neurons increase their activity in response to arousing stimuli like rewards and stressors (17). The functional effects of this pattern of neuropeptide coexpression on brain reward systems, and, in turn, on motivated behavior, are poorly understood because orexin and dynorphin are not traditionally studied together. Given their opposing effects on behavior and neuronal physiology when studied alone, it can be hypothesized that dominance in the effects of one peptide over the other could cause widely divergent behavioral phenotypes in reward sensitivity. For example, dominant orexin signaling may enhance reward sensitivity and reward seeking, whereas dominant dynorphin signaling may result in decreased reward sensitivity and anergia. Because these states have major relevance to psychiatric illnesses like addiction and depression, where reward processing is disordered, we sought ...

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Section: Orexin and Dynorphin Can Exert Balanced Opposing Effects Onmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

Muschamp

Hollander

Thompson

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

216

213

View full text Add to dashboard Cite

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“…Administration of orexin has been shown to affect multiple reward-seeking behaviors, including operant responding for high-fat pellets and sucrose, conditioned place preference (CPP) for food, cue-induced reinstatement of extinguished sucroseseeking, and food-reinforced responding under both variable and progressive ratio schedules of reinforcement (Harris et al, 2005;Cason et al, 2010;Sharf et al, 2010). These studies use the partial OX 1 SORA SB-334867 to suggest the involvement of OX 1 receptors in reward-based feeding.…”

Section: A Central Modulation Of Behavior and Physiology By Orexin Smentioning

confidence: 99%

“…Borgland et al (2006) expanded upon these studies and linked orexin signaling with synaptic plasticity in VTA dopamine neurons and behavioral sensitization to cocaine. On the basis of these studies, a vast body of preclinical research has evolved around orexin signaling in addictive behaviors Lawrence, 2010;Sharf et al, 2010;Zhou et al, 2011). Together, these studies have indicated the potential for blocking drug-seeking behaviors through antagonism of orexin signaling, suggesting orexin receptor antagonists as possible therapeutics for treating addiction to a variety of abusive drugs, including cocaine, amphetamine, alcohol, and morphine.…”

Section: A Central Modulation Of Behavior and Physiology By Orexin Smentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

et al. 2012

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“…In parallel, evidence has accumulated that demonstrates an involvement of OX signaling via OX1R in reward pathways associated with drug dependence (Sharf et al, 2010). The role of the OX1R in emotional behavior is emerging .…”

Section: Introductionmentioning

confidence: 99%

A Selective Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal without Hypnotic Effects

Bonaventure

Yun

Johnson

et al. 2015

J Pharmacol Exp Ther

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Orexins (OXs) are peptides produced by perifornical (PeF) and lateral hypothalamic neurons that exert a prominent role in arousal-related processes, including stress. A critical role for the orexin-1 receptor (OX1R) in complex emotional behavior is emerging, such as overactivation of the OX1R pathway being associated with panic or anxiety states. Here we characterize a brain-penetrant, selective, and high-affinity OX1R antagonist, Although compound 56 did not alter spontaneous sleep in rats and in wildtype mice, its administration in orexin-2 receptor knockout mice selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. In a rat model of psychological stress induced by cage exchange, the OX1R antagonist prevented the prolongation of sleep onset without affecting sleep duration. In a rat model of panic vulnerability (involving disinhibition of the PeF OX region) to threatening internal state changes (i.e., intravenous sodium lactate infusion), compound 56 attenuated sodium lactate-induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. In conclusion, OX1R antagonism represents a novel therapeutic strategy for the treatment of various psychiatric disorders associated with stress or hyperarousal states.

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Role of orexin/hypocretin in dependence and addiction

Cited by 95 publications

References 81 publications

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

A Selective Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal without Hypnotic Effects

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