Orexin-1 receptor antagonism does not reduce the rewarding potency of cocaine in Swiss–Webster mice

Riday, Thorfinn T.; Fish, Eric W.; Robinson, J. Elliott; Jarrett, Thomas M.; McGuigan, Megan M.; Malanga, C. J.

doi:10.1016/j.brainres.2011.11.003

Cited by 15 publications

(12 citation statements)

References 65 publications

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“…Although this effect may be related to the unique pharmacodynamics of norBNI and other prototypical KOR antagonists (10), it may also indicate that there is redundancy in processes that modulate the activity of brain reward circuits or that phasic increases in orexin tone alone (unopposed by coreleased dynorphin) are insufficient to convey a reward signal from the stimulation site in the lateral hypothalamus. These findings may at first seem inconsistent with the work of others who examined SB334867 on ICSS threshold during the dark phase (21). However, there is considerable evidence that decreases in orexin function can have consequences that depend on whether animals are tested during their light or dark phase.…”

Section: Resultscontrasting

confidence: 63%

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.

222

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: Resultscontrasting

confidence: 63%

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.

222

213

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“…In contrast, wild-type mice given an orexin 1 receptor antagonist and orexin knock-out mice display normal sensitization and locomotor response to morphine (Sharf et al, 2010). Also, orexin 1 receptor blockade fails to affect cocaine potentiation of brain stimulation-induced reward in mice (Riday et al, 2012).…”

Section: Discussionmentioning

confidence: 98%

Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling

Valdivia¹,

Cornejo²,

Reynaldo³

et al. 2015

Psychoneuroendocrinology

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Please cite this article in press as: Valdivia, S., et al., Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling. Psychoneuroendocrinology (2015) and time-limited exposed to a high-fat diet (HFD) display robust binge eating events that gradually escalate over the initial accesses. Intake escalation is proposed to be part of the transition from a controlled to a compulsive or loss of control behavior. Here, we used a combination of behavioral and neuroanatomical studies in mice daily and time-limited exposed to HFD to determine the neuronal brain targets that are activated -as indicated by the marker of cellular activation c-Fos -under these circumstances. Also, we used pharmacologically or genetically manipulated mice to study the role of orexin or ghrelin signaling, respectively, in the modulation of this behavior. We found that four daily and time-limited accesses to HFD induce: (i) a robust hyperphagia with an escalating profile, (ii) an activation of different sub-populations of the ventral tegmental area dopamine neurons and accumbens neurons that is, in general, more pronounced than the activation observed after a single HFD consumption event, and (iii) an activation of the hypothalamic orexin neurons, although orexin signaling blockage fails to affect escalation of HFD intake. In addition, we found that ghrelin receptor-deficient mice fail to both escalate the HFD consumption over the successive days of exposure and fully induce activation of the mesolimbic pathway in response to HFD consumption. Current data suggest that the escalation in high fat intake during repeated accesses differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling.

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“…Conversely, direct injection of OX-A into the ventral tegmental area is sufficient to reinstate an extinguished place preference (Tung et al, 2016). Further, cocaine-induced lowering of the intracranial self-stimulation threshold is also found to be reversed by systemic injection of SB-334867 in rats (Hollander et al, 2012), although this was not found to occur using a higher dose in mice (Riday et al, 2012). Overall, these results support a role for OX in the reward from cocaine intake.…”

Section: Role Of Orexin/hypocretin In Non-homeostatic Intakementioning

confidence: 99%

Orexin/Hypocretin System: Role in Food and Drug Overconsumption

Barson

Leibowitz

2017

International Review of Neurobiology

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The neuropeptide orexin/hypocretin (OX), while largely transcribed within the hypothalamus, is released throughout the brain to affect complex behaviors. Primarily through the hypothalamus itself, OX homeostatically regulates adaptive behaviors needed for survival, including food intake, sleep-wake regulation, mating, and maternal behavior. However, through extra-hypothalamic limbic brain regions, OX promotes seeking and intake of rewarding substances of abuse, like palatable food, alcohol, nicotine, and cocaine. This neuropeptide, in turn, is stimulated by the intake of or early life exposure to these substances, forming a non-homeostatic, positive feedback loop. The OX receptor involved in these behaviors, adaptive behavior or substance seeking and intake, is dependent on the particular brain region that contributes to them. Thus, we propose that, while the primary function of OX is to maintain arousal for the performance of adaptive behaviors, this neuropeptide system is readily coopted by rewarding substances that involve positive feedback, ultimately promoting their abuse.

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Orexin-1 receptor antagonism does not reduce the rewarding potency of cocaine in Swiss–Webster mice

Cited by 15 publications

References 65 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

Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling

Orexin/Hypocretin System: Role in Food and Drug Overconsumption

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