Hypocretin/Orexin Signaling in the Hypothalamic Paraventricular Nucleus is Essential for the Expression of Nicotine Withdrawal

Plaza-Zabala, Ainhoa; Flores, África; Maldonado, Rafaël; Berrendero, Fernando

doi:10.1016/j.biopsych.2011.06.025

Cited by 79 publications

(64 citation statements)

References 60 publications

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“…In sum, the results of the present study hint at a role of the orexin system in cannabis as well as nicotine dependence in comparison to healthy and nonaddicted controls. This is in line with findings in the literature that the orexin system plays a major role in the reinforcing effects of several drugs of abuse such as opioids, nicotine and alcohol; orexins are also associated with the neurobiological mechanisms underlying behaviors from relapse to drug-seeking that might be influenced by drug-related environmental stimuli and stress [24]. …”

Section: Discussionsupporting

confidence: 75%

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Orexin A Expression and Promoter Methylation in Patients with Cannabis Dependence in Comparison to Nicotine-Dependent Cigarette Smokers and Nonsmokers

Rotter¹,

Bayerlein²,

Hansbauer³

et al. 2012

Neuropsychobiology

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Background: The orexins (hypocretins) are neuropeptides with an origin in the lateral hypothalamus. They have been found to be crucial within the context of drug craving, withdrawal und relapse. Methods: Therefore, orexin A gene expression and promoter methylation in peripheral blood cells of 77 subjects [36 with tetrahydrocannabinol (THC) dependence, 20 nicotine-dependent cigarette smokers and 21 nonsmokers] were assessed by quantitative real-time PCR and methylation-specific digestion PCR. Results: There was a statistically significant difference in orexin A expression between the three groups [p = 0.000, F = 131.4, d.f. = 2, analysis of variance (ANOVA)]. Orexin A gene expression was statistically significantly correlated with the Satisfaction with Life Scale (r = –0.28, p = 0.018), a visual analogue scale of craving (r = 0.734, p = 0.000) and three subscales of the World Health Organization Alcohol, Smoking and Substance Involvement Screening Test, i.e. nicotine consumption (r = 0.388, p = 0.001), alcohol consumption (r = 0.354, p = 0.002) and cannabis consumption (r = 0.783, p = 0.000). The mean promoter methylation (as a percentage) was not statistically related to orexin gene expression. However, there was a statistically significant difference in promoter methylation with regard to body mass index in general (F = 2.37, d.f. = 54, p = 0.016, ANOVA). Conclusions: Orexin might be a possible target in THC as well as nicotine dependence, taking into account the effect of THC on energy homeostasis in the circuit of reward and motivation and its impact on appetite and body weight.

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Section: Discussionsupporting

confidence: 75%

“…Furthermore, orexin signalling seems to play a critical role in nicotine addiction and withdrawal, as has been shown in animal research [24]. …”

Section: Introductionmentioning

confidence: 99%

Orexin A Expression and Promoter Methylation in Patients with Cannabis Dependence in Comparison to Nicotine-Dependent Cigarette Smokers and Nonsmokers

Rotter¹,

Bayerlein²,

Hansbauer³

et al. 2012

Neuropsychobiology

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“…Systemic SB-334867 administration reduces nicotine self-administration [137], cue-induced reinstatement [138] and orexin-A induced reinstatement of nicotine-seeking [139]. Systemic SB-334867, but not TCS OX2 29, reduces signs of mecamylamine-induced nicotine withdrawal [140] and the operant acquisition, self-administration and break-point for a synthetic cannabinoid agonist, WIN55,212-2 [141]. Additionally, there is emerging evidence for interactions between the orexin system and endogenous cannabinoid signalling [19,36,142] and orexin-A expression is downregulated in tetrahydrocannabinol-dependent patients [143].…”

Section: Orexin and Nicotine And Cannabinoidsmentioning

confidence: 95%

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

Khoo

Brown

2014

CNS Drugs

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Addiction is a chronic relapsing disorder which presents a significant global health burden and unmet medical need. The orexin/hypocretin system is an attractive potential therapeutic target as demonstrated by the successful clinical trials of antagonist medications like Suvorexant for insomnia. It is composed of two neuropeptides, orexin-A and orexin-B and two excitatory and promiscuous G-protein coupled receptors, OX1 and OX2. Orexins are known to have a variety of functions, most notably in regulating arousal, appetite and reward. The orexins have been shown to have a role in mediating the effects of several drugs of abuse, such as cocaine, morphine and alcohol via projections to key brain regions such as the ventral tegmental area, nucleus accumbens and prefrontal cortex. However, it has not yet been demonstrated whether the dual orexin receptor antagonists (DORAs) under development for insomnia are ideal drugs for the treatment of addiction. The question of whether to use a DORA or single orexin receptor antagonist (SORA) for the treatment of addiction is a key question that will need to be answered in order to maximize the clinical utility of orexin receptor antagonists. This review will examine the role of the orexin/hypocretin system in addiction, orexin-based pharmacotherapies under development and factors affecting the selection of one or both orexin receptors as drug targets for the treatment of addiction.

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“…Morphine withdrawal-induced activation of the PVN, BNST, and CeA is decreased by systemic HcrtR1 blockade [27], and local HcrtR1 antagonism in the PVN reduces the behavioral expression of nicotine withdrawal [28]. These findings raise the possibility that Hcrt modulation of CRF neurons participates in the chronically-relapsing, negative affective state that characterizes drug addiction.…”

Section: Hypocretin Interactions With Crf Stress Pathwaysmentioning

confidence: 99%

Hypocretin (orexin) neuromodulation of stress and reward pathways

Giardino¹,

Lecea²

2014

Current Opinion in Neurobiology

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Hypocretin (also known as orexin) is a peptide neuromodulator that is expressed exclusively in the lateral hypothalamic area and plays a fundamental role in wakefulness and arousal. Chronic stress and compulsive drug-seeking are two examples of dysregulated states of hyperarousal that are influenced by hypocretin transmission throughout hypothalamic, extended amygdala, brainstem, and mesolimbic pathways. Here, we review current advances in the understanding of hypocretin's modulatory actions underlying conditions of negative and positive emotional valence, focusing particularly on mechanisms that facilitate adaptive (and maladaptive) responses to stressful or rewarding environmental stimuli. We conclude by discussing progress toward integrated theories for hypocretin modulation of divergent behavioral domains.

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Hypocretin/Orexin Signaling in the Hypothalamic Paraventricular Nucleus is Essential for the Expression of Nicotine Withdrawal

Abstract: These data demonstrate that hypocretin signaling acting on Hcrtr-1 in the PVN plays a crucial role in the expression of nicotine withdrawal.

Cited by 79 publications

References 60 publications

Orexin A Expression and Promoter Methylation in Patients with Cannabis Dependence in Comparison to Nicotine-Dependent Cigarette Smokers and Nonsmokers

Orexin A Expression and Promoter Methylation in Patients with Cannabis Dependence in Comparison to Nicotine-Dependent Cigarette Smokers and Nonsmokers

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

Hypocretin (orexin) neuromodulation of stress and reward pathways

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