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Effects of Suvorexant, a Dual Orexin/Hypocretin Receptor Antagonist, on Impulsive Behavior Associated with Cocaine.

ABSTRACT: Hypothalamic hypocretin (orexin) peptides mediate arousal, attention, and reward processing. Fibers containing orexins project to brain structures that govern motivated behavior, including the ventral tegmental area (VTA). A number of psychiatric conditions, including attention deficit hyperactivity disorder (ADHD) and substance use disorders, are characterized by deficits in impulse control, however the relationship between orexin and impulsive behavior is incompletely characterized. The effects of systemic or centrally administered orexin receptor (OXR) antagonists on measures of impulsive-like behavior in rats were evaluated using the five-choice serial reaction time task (5-CSRTT) and delay discounting procedures. These paradigms were also used to test the capacity of OXR antagonists to attenuate acute cocaine-evoked impulsivity. Finally, immunohistochemistry and calcium imaging were used to assess potential cellular mechanisms by which OXR blockade may influence motor impulsivity. Suvorexant, a dual (OX_1/2R) orexin receptor antagonist, reduced cocaine-evoked premature responses in 5-CSRTT when administered systemically or directly into VTA. Neither suvorexant nor OX₁R- or OX₂R-selective compounds (SB334867 or TCS-OX2-29, respectively) altered delay discounting. Finally, suvorexant did not alter Fos-immunoreactivity within tyrosine hydroxylase-immunolabeled neurons of VTA, but did attenuate cocaine- and orexin-induced increases in calcium transient amplitude within neurons of VTA. Results from the present studies suggest potential therapeutic utility of OXR antagonists in reducing psychostimulant-induced motor impulsivity. These findings also support the view that orexin transmission is closely involved in executive function in normal and pathological conditions.

SUBMITTER: Gentile TA

PROVIDER: S-EPMC5854790 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Effects of Suvorexant, a Dual Orexin/Hypocretin Receptor Antagonist, on Impulsive Behavior Associated with Cocaine.

Gentile Taylor A TA Simmons Steven J SJ Watson Mia N MN Connelly Krista L KL Brailoiu Eugen E Zhang Yanan Y Muschamp John W JW

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20170725 5

Hypothalamic hypocretin (orexin) peptides mediate arousal, attention, and reward processing. Fibers containing orexins project to brain structures that govern motivated behavior, including the ventral tegmental area (VTA). A number of psychiatric conditions, including attention deficit hyperactivity disorder (ADHD) and substance use disorders, are characterized by deficits in impulse control, however the relationship between orexin and impulsive behavior is incompletely characterized. The effect ...[more]

PMID: 28741623

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Project description:Study objectivesSuvorexant (MK-4305) is an orexin receptor antagonist being developed for the treatment of insomnia. This report describes the effects of nighttime administration of suvorexant on polysomnography (PSG) sleep parameters in healthy young men.DesignRandomized, double-blind, placebo-controlled, 4-period crossover PSG study, followed by an additional 5(th) period to assess pharmacokinetics.SettingSleep laboratory.ParticipantsHealthy young men between 18 and 45 years of age (22 enrolled, 19 completed).InterventionsPeriods 1-4: suvorexant (10 mg, 50 mg, or 100 mg) or placebo 1 h before nighttime PSG recording. Period 5: suvorexant 10 mg, 50 mg, or 100 mg.Measurements and resultsIn Periods 1-4, overnight sleep parameters were recorded by PSG and next-morning residual effects were assessed by psychomotor performance tests and subjective assessments. Statistically significant sleep-promoting effects were observed with all doses of suvorexant compared to placebo. Suvorexant 50 mg and 100 mg significantly decreased latency to persistent sleep and wake after sleep onset time, and increased sleep efficiency. Suvorexant 10 mg significantly decreased wake after sleep onset time. There were no statistically significant effects of suvorexant on EEG frequency bands including delta (slow wave) activity based on power spectral analysis. Suvorexant was well tolerated. There was no evidence of next-day residual effects for suvorexant 10 mg. Suvorexant 50 mg statistically significantly reduced subjective alertness, and suvorexant 100 mg significantly increased reaction time and reduced subjective alertness. There were no statistically significant effects of any suvorexant dose on digit symbol substitution test performance. In Period 5, plasma samples of suvorexant were collected for pharmacokinetic evaluation. The median T(max) was 3 hours and apparent terminal t(½) was 9-13 hours.ConclusionsIn healthy young men without sleep disorders, suvorexant promoted sleep with some evidence of residual effects at the highest doses.

Dataset Information

Effects of Suvorexant, a Dual Orexin/Hypocretin Receptor Antagonist, on Impulsive Behavior Associated with Cocaine.

Publications

Effects of Suvorexant, a Dual Orexin/Hypocretin Receptor Antagonist, on Impulsive Behavior Associated with Cocaine.

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