Sensitivity of Hypocretin System to Chronic Alcohol Exposure: A Human and Animal Study

McGregor, Ronald L.; Matzeu, Alessandra; Thannickal, Thomas C.; Wu, Frank; Cornford, Marcia E.; Martin‐Fardon, Rémi; Siegel, Jerome M.

doi:10.1016/j.neuroscience.2023.04.018

Cited by 6 publications

(1 citation statement)

References 87 publications

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“…As we did not include a non-HPF intake control group, we can only conclude that the additional exposure to dieting periods and stress did not lead to increased, long-lasting hypothalamic OXA peptide expression and recruitment of the proposed "reserve pool" of orexin neurons (James & Aston-Jones, 2022) as was previously reported in response to chronic opiate or cocaine exposure (James et al, 2019;Thannickal et al, 2018). Chronic exposure to alcohol, however, for example, does also not change OXA expression in the hypothalamus of rats (McGregor et al, 2023).…”

Section: Discussionmentioning

confidence: 61%

Evaluating the efficacy of the selective orexin 1 receptor antagonist nivasorexant in an animal model of binge‐eating disorder

Steiner,

Botticelli,

Bergamini

et al. 2024

Intl J Eating Disorders

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ObjectiveTest the efficacy of the selective orexin 1 receptor (OX1R) antagonist (SO1RA) nivasorexant in an animal model of binge‐eating disorder (BED) and study its dose–response relationship considering free brain concentrations and calculated OX1R occupancy. Compare nivasorexant's profile to that of other, structurally diverse SO1RAs. Gain understanding of potential changes in orexin‐A (OXA) neuropeptide and deltaFosB (ΔFosB) protein expression possibly underlying the development of the binge‐eating phenotype in the rat model used.MethodBinge‐like eating of highly palatable food (HPF) in rats was induced through priming by intermittent, repeated periods of dieting and access to HPF, followed by an additional challenge with acute stress. Effects of nivasorexant were compared to the SO1RAs ACT‐335827 and IDOR‐1104‐2408. OXA expression in neurons and neuronal fibers as well as ΔFosB and OXA‐ΔFosB co‐expression was studied in relevant brain regions using immuno‐ or immunofluorescent histochemistry.ResultsAll SO1RAs dose‐dependently reduced binge‐like eating with effect sizes comparable to the positive control topiramate, at unbound drug concentrations selectively blocking brain OX1Rs. Nivasorexant's efficacy was maintained upon chronic dosing and under conditions involving more frequent stress exposure. Priming for binge‐like eating or nivasorexant treatment resulted in only minor changes in OXA or ΔFosB expression in few brain areas.DiscussionSelective OX1R blockade reduced binge‐like eating in rats. Neither ΔFosB nor OXA expression proved to be a useful classifier for their binge‐eating phenotype. The current results formed the basis for a clinical phase II trial in BED, in which nivasorexant was unfortunately not efficacious compared with placebo.Public SignificanceNivasorexant is a new investigational drug for the treatment of binge‐eating disorder (BED). It underwent clinical testing in a phase II proof of concept trial in humans but was not efficacious compared with placebo. The current manuscript investigated the drug's efficacy in reducing binge‐like eating behavior of a highly palatable sweet and fat diet in a rat model of BED, which initially laid the foundation for the clinical trial.

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