Multiple roles for orexin/hypocretin in addiction

Mahler, Stephen V.; Smith, Rachel J.; Moorman, David E.; Sartor, Gregory C.; Aston‐Jones, Gary

doi:10.1016/b978-0-444-59489-1.00007-0

Cited by 194 publications

(214 citation statements)

References 321 publications

(501 reference statements)

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“…Orexin has also been implicated in nonfood rewards such as addictive drugs (Harris et al, 2005;Harris and Aston-Jones, 2006;Aston-Jones et al, 2010;Smith et al, 2010b;Kim et al, 2012;Mahler et al, 2012). Involvement in drug rewards raises the possibility that the VP orexin hotspot identified here might also have a role in generating intense drug pleasures, and possibly of other non-ingestive sensory rewards.…”

Section: Circuit and Clinical Implicationsmentioning

confidence: 96%

“…Clinically, regulatory LH and orexin interactions with VP and related hedonic food reward circuits highlighted here may therefore be relevant to understanding some forms of obesity and binge-eating disorders (Aston-Jones et al, 2010;Choi et al, 2010;Mahler et al, 2012). Such roles for VP in hedonic dysfunction pathological over-consumption might also possibly extend to compulsive pursuits of other rewards, including drug addiction (Mahler et al, 2012).…”

Section: Circuit and Clinical Implicationsmentioning

confidence: 99%

“…Orexin has been implicated in mediating hunger (Harris et al, 2005;Zheng et al, 2007;Berthoud and Morrison, 2008;Gao and Horvath, 2008;Borgland et al, 2009;Aston-Jones et al, 2010;Choi et al, 2010;Berthoud et al, 2011;Thompson and Borgland, 2011;Mahler et al, 2012), and it seems relevant to speculate that an orexin hedonic hotspot in posterior VP, demonstrated by exogenous stimulation here, might also permit any orexin elevations in VP hotspot that occur endogenously during hunger make foods taste better (alliesthesia). Elevation in endogenous orexin release, triggered by NPY released on LH neurons during hunger, could amplify food hedonic impact just as exogenous microinjections of orexin in the VP hotspot did here.…”

Section: Potential Relations To Orexin Function In Reward and Alliestmentioning

confidence: 99%

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An Orexin Hotspot in Ventral Pallidum Amplifies Hedonic ‘Liking’ for Sweetness

Berridge

2013

Neuropsychopharmacol

150

101

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Orexin (hypocretin) is implicated in stimulating appetite as well as arousal, and in both food reward and drug reward. The ventral pallidum (VP) receives orexin projections from lateral hypothalamus neurons (LH), and orexin terminals are especially dense in the posterior half of VP, which is also the location of an opioid hedonic hotspot. The VP hotspot is a roughly cubic-millimeter site where mu opioid stimulation can amplify the hedonic impact of sweetness, expressed as an increase in 'liking' reactions to sucrose taste. The anatomical overlap in posterior VP between opioid hotspot and orexin inputs raises the possibility that the hedonic hotspot might allow orexin to amplify 'liking' too. We examined whether microinjections of orexin-A into the VP hotspot enhance the hedonic impact of sucrose, as assessed via affective taste reactivity measures of 'liking' reactions, and additionally compared effects at nearby sites in adjacent LH and extended amygdala. Taste reactivity results indicated that orexin stimulation specifically in the VP hotspot nearly doubled the magnitude of positive 'liking' reactions elicited by the taste of sucrose. Mapping results for localization of function, aided by Fos plume measures of the local spread of orexin impact, suggested that hedonic enhancement was generated by essentially the same cubicmillimeter of posterior VP previously identified as the opioid hotspot. By contrast, microinjection sites in the anterior half of VP, or in LH or extended amygdala, generally failed to produce any hedonic enhancement. We conclude that an orexin hedonic hotspot exists in posterior VP, with similar boundaries to the opioid hotspot. An orexin hedonic hotspot may permit regulatory hypothalamic circuitry to make foods more 'liked' during hunger by acting through VP. Dysfunction in a VP orexin hotspot in addiction or mood disorders might also contribute to some types of affective psychopathology.

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Section: Circuit and Clinical Implicationsmentioning

confidence: 96%

Section: Circuit and Clinical Implicationsmentioning

confidence: 99%

Section: Potential Relations To Orexin Function In Reward and Alliestmentioning

confidence: 99%

See 1 more Smart Citation

An Orexin Hotspot in Ventral Pallidum Amplifies Hedonic ‘Liking’ for Sweetness

Berridge

2013

Neuropsychopharmacol

150

101

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“…The hypocretin/orexin (HCRT) neuropeptides have recently been associated with both stress and drug-seeking behaviors (for review, see Johnson et al, 2012;Mahler et al, 2012). These neuropeptides consist of HCRT-1 and HCRT-2 (also known as orexin A and orexin B, respectively) and are synthesized solely within a restricted region of the dorsal hypothalamus, including the lateral hypothalamus proper, adjacent perifornical area, and dorsomedial hypothalamus (de Lecea et al, 1998; Sakurai et al, 1998), collectively referred to as the lateral hypothalamic area (LHA).…”

Section: Introductionmentioning

confidence: 99%

Hypocretin Receptor 2 Antagonism Dose-Dependently Reduces Escalated Heroin Self-Administration in Rats

Schmeichel

Barbier

Misra

et al. 2014

Neuropsychopharmacol

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The hypocretin/orexin (HCRT) system has been associated with both positive and negative drug reinforcement, implicating HCRT receptor 1 (HCRT-R1) signaling in drug-related behaviors for all major drug classes, including opioids. However, to date there are limited studies investigating the role of HCRT receptor 2 (HCRT-R2) signaling in compulsive-like drug seeking. Escalation of drug intake with extended access has been suggested to model the transition from controlled drug use to compulsive-like drug seeking/taking. The current study examined the effects of a HCRT-R2 antagonist, NBI-80713, on heroin self-administration in rats allowed short-(1 h; ShA) or long-(12 h; LgA) access to intravenous heroin self-administration. Results indicate that systemically administered NBI-80713 dose-dependently decreased heroin self-administration in LgA, but not in ShA, animals. Quantitative PCR analyses showed an increase in Hcrtr2 mRNA levels in the central amygdala, a stress-related brain region, of LgA rats. These observations suggest a functional role for HCRT-R2 signaling in compulsive-like heroin self-administration associated with extended access and indicate HCRT-R2 antagonism as a potential pharmacological target for the treatment of heroin dependence.

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“…According to our behavioral results, systemic injection of THC increased extracellular dopamine levels in the NAc in WT animals, but this effect was blocked in Hcrtr-1 KO mice. VTA hypocretin signaling seems to be particularly important in the regulation of drug reward seeking behavior (42). Thus, the VTA shows high density of hcrtr-1 (28,43), hypocretin-1 induces a direct depolarization of VTA dopamine neurons (44), and the intra-VTA infusion of hypocretin-1 increases dopamine levels in the NAc (43,45).…”

Section: The Enhanced Of Dopamine Extracellular Levels In the Nucleusmentioning

confidence: 99%

The Hypocretin/Orexin Receptor-1 as a Novel Target to Modulate Cannabinoid Reward

Flores

Maldonado

Berrendero

2014

Biological Psychiatry

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Table 1) 2 Background: Cannabis is the most widely used illicit drug in the world. Although there is a high prevalence of users who seek treatment for cannabis dependence, no accepted pharmacological treatment is still available to facilitate and maintain abstinence. The hypocretin/orexin system plays a critical role in drug addiction and the potential participation of this system in the addictive properties of cannabinoids is still unknown. Methods:We investigated the effects of hypocretins in the intravenous selfadministration of the synthetic cannabinoid agonist WIN55,212-2 using hypocretin receptor-1 (Hcrtr-1) and hypocretin receptor-2 (Hcrtr-2) antagonists, and Hcrtr-1 knockout mice. Additional groups of mice were trained to obtain water to rule out operant responding impairments. Activation of hypocretin neurons was analyzed by using double label immunofluorescence of FosB/∆FosB with hypocretin-1.Microdialysis studies were performed to evaluate dopamine extracellular levels in the nucleus accumbens after acute ∆ 9 -tetrahydrocannabinol (THC) administration.Results: Systemic administration of the Hcrtr-1 antagonist SB334867, but not the Hctr-2 antagonist TCSOX229, reduced intravenous self-administration of WIN55,212-2 as well as the maximum effort to obtain a WIN55,212-2 infusion as revealed under a progressive ratio schedule. This role of Hcrtr-1 in the reinforcing and motivational properties of WIN55,212-2 was confirmed in Hcrtr-1 knockout mice. Contingent, but not non-contingent WIN55,212-2 self-administration increased the percentage of hypocretin cells expressing FosB/∆FosB in the lateral hypothalamus. The enhancement in dopamine extracellular levels in the nucleus accumbens induced by THC was blocked in mice lacking the Hcrtr-1.Conclusions: These findings demonstrate that Hcrtr-1 modulates the reinforcing properties of cannabinoids, which could have a clear therapeutic interest. 3 IntroductionCannabis is the most used illicit drug worldwide (1). It is estimated that about 9% of those who ever use this drug become daily users (2), rising to 16% when the consumption is initiated during the adolescence (2). Recent analysis of cannabis extracts has shown an increase in potency over the last years due to enhanced content of ∆ 9 -tetrahydrocannabinol (THC), its primary psychoactive constituent (3). A high THC content leads to an increase in the subjective effects of this drug probably enhancing the risk of dependence and psychotic symptoms of cannabis users (3). Treatment admissions for cannabis-use disorders have progressively increased in the past decade.Approximately 90% of those seeking treatment for these disorders have great difficulty achieving and sustaining periods of abstinence (4), and the majority relapse to use following therapeutic interventions (5). There are currently no effective pharmacotherapeutic approaches for this disorder (5). Therefore, the need for identifying specific medications to improve treatment outcomes for cannabis dependence becomes a major clinical priority.Several findin...

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Multiple roles for orexin/hypocretin in addiction

Cited by 194 publications

References 321 publications

An Orexin Hotspot in Ventral Pallidum Amplifies Hedonic ‘Liking’ for Sweetness

An Orexin Hotspot in Ventral Pallidum Amplifies Hedonic ‘Liking’ for Sweetness

Hypocretin Receptor 2 Antagonism Dose-Dependently Reduces Escalated Heroin Self-Administration in Rats

The Hypocretin/Orexin Receptor-1 as a Novel Target to Modulate Cannabinoid Reward

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