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

Overview

Journal Neuropsychopharmacology

Date 2017 Jul 26

PMID 28741623

Citations 29

Authors

Taylor A Gentile

Steven J Simmons

Mia N Watson

Krista L Connelly

Eugen Brailoiu

Yanan Zhang

John W Muschamp

Affiliations

Soon will be listed here.

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 (OXR) orexin receptor antagonist, reduced cocaine-evoked premature responses in 5-CSRTT when administered systemically or directly into VTA. Neither suvorexant nor OXR- or OXR-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.

Citing Articles

Genetic associations between orexin genes and phenotypes related to behavioral regulation in humans, including substance use.

Aliev F, De Sa Nogueira D, Aston-Jones G, Dick D Mol Psychiatry. 2025; .

PMID: 39880903 DOI: 10.1038/s41380-025-02895-4.

Doxorubicin treatment has a biphasic effect over time on dopamine release and impulsive behavior in Wistar rats.

Garcia K, Theismann J, Schneider T, LeComte R, Jarmolowicz D, Johnson M Naunyn Schmiedebergs Arch Pharmacol. 2025; .

PMID: 39820646 DOI: 10.1007/s00210-024-03766-5.

The Role of Orexin Receptor Antagonists in Inhibiting Drug Addiction: A Review Article.

Esmaili-Shahzade-Ali-Akbari P, Ghaderi A, Sadeghi A, Nejat F, Mehramiz A Addict Health. 2024; 16(2):130-139.

PMID: 39051042 PMC: 11264478. DOI: 10.34172/ahj.2024.1491.

Embryonic ethanol exposure and optogenetic activation of hypocretin neurons stimulate similar behaviors early in life associated with later alcohol consumption.

Collier A, Yasmin N, Karatayev O, Abdulai A, Yu B, Fam M Sci Rep. 2024; 14(1):3021.

PMID: 38321123 PMC: 10847468. DOI: 10.1038/s41598-024-52465-x.

Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control.

Bandarabadi M, Li S, Aeschlimann L, Colombo G, Tzanoulinou S, Tafti M Mol Psychiatry. 2023; 29(2):327-341.

PMID: 38123729 PMC: 11116111. DOI: 10.1038/s41380-023-02329-z.

References

Vall G, Gutierrez F, Peri J, Garriz M, Ferraz L, Bailles E . Seven basic dimensions of personality pathology and their clinical consequences: Are all personalities equally harmful?. Br J Clin Psychol. 2015; 54(4):450-68. DOI: 10.1111/bjc.12091. View

de Wit H . Impulsivity as a determinant and consequence of drug use: a review of underlying processes. Addict Biol. 2008; 14(1):22-31. PMC: 3640851. DOI: 10.1111/j.1369-1600.2008.00129.x. View

Borgland S, Taha S, Sarti F, Fields H, Bonci A . Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron. 2006; 49(4):589-601. DOI: 10.1016/j.neuron.2006.01.016. View

Jhou T, Geisler S, Marinelli M, Degarmo B, Zahm D . The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta. J Comp Neurol. 2009; 513(6):566-96. PMC: 3116663. DOI: 10.1002/cne.21891. View

Lambe E, Olausson P, Horst N, Taylor J, Aghajanian G . Hypocretin and nicotine excite the same thalamocortical synapses in prefrontal cortex: correlation with improved attention in rat. J Neurosci. 2005; 25(21):5225-9. PMC: 6724823. DOI: 10.1523/JNEUROSCI.0719-05.2005. View

Robbins T . The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl). 2002; 163(3-4):362-80. DOI: 10.1007/s00213-002-1154-7. View

Zhu Y, Miwa Y, Yamanaka A, Yada T, Shibahara M, Abe Y . Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins. J Pharmacol Sci. 2003; 92(3):259-66. DOI: 10.1254/jphs.92.259. View

Evenden J . Varieties of impulsivity. Psychopharmacology (Berl). 1999; 146(4):348-61. DOI: 10.1007/pl00005481. View

Carter M, De Lecea L, Adamantidis A . Functional wiring of hypocretin and LC-NE neurons: implications for arousal. Front Behav Neurosci. 2013; 7:43. PMC: 3657625. DOI: 10.3389/fnbeh.2013.00043. View

10.

Korotkova T, Sergeeva O, Eriksson K, Haas H, Brown R . Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci. 2003; 23(1):7-11. PMC: 6742159. View

11.

Bari A, Dalley J, Robbins T . The application of the 5-choice serial reaction time task for the assessment of visual attentional processes and impulse control in rats. Nat Protoc. 2008; 3(5):759-67. DOI: 10.1038/nprot.2008.41. View

12.

Roecker A, Cox C, Coleman P . Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia. J Med Chem. 2015; 59(2):504-30. DOI: 10.1021/acs.jmedchem.5b00832. View

13.

Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli R, Tanaka H . Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998; 92(4):573-85. DOI: 10.1016/s0092-8674(00)80949-6. View

14.

Scammell T, Winrow C . Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol. 2010; 51:243-66. PMC: 3058259. DOI: 10.1146/annurev-pharmtox-010510-100528. View

15.

Muschamp J, Hollander J, Thompson J, Voren G, Hassinger L, Onvani S . Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area. Proc Natl Acad Sci U S A. 2014; 111(16):E1648-55. PMC: 4000785. DOI: 10.1073/pnas.1315542111. View

16.

Peyron C, Tighe D, van den Pol A, de Lecea L, Heller H, Sutcliffe J . Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998; 18(23):9996-10015. PMC: 6793310. View

17.

Alcaraz-Iborra M, Cubero I . Do Orexins contribute to impulsivity-driven binge consumption of rewarding stimulus and transition to drug/food dependence?. Pharmacol Biochem Behav. 2015; 134:31-4. DOI: 10.1016/j.pbb.2015.04.012. View

18.

Martin L, Potts G . Reward sensitivity in impulsivity. Neuroreport. 2004; 15(9):1519-22. DOI: 10.1097/01.wnr.0000132920.12990.b9. View

19.

Smart D, Brough S, Jewitt F, Johns A, Porter R, Jerman J . SB-334867-A: the first selective orexin-1 receptor antagonist. Br J Pharmacol. 2001; 132(6):1179-82. PMC: 1572677. DOI: 10.1038/sj.bjp.0703953. View

20.

Harris G, Wimmer M, Aston-Jones G . A role for lateral hypothalamic orexin neurons in reward seeking. Nature. 2005; 437(7058):556-9. DOI: 10.1038/nature04071. View