Improvement of Autistic-like Behaviors in Adult Rats Prenatally Exposed to Valproic Acid Through Early Suppression of Orexin Receptor

Overview

Journal Ann Med Surg (Lond)

Publisher Wolters Kluwer

Specialty Medical Education

Date 2024 Jan 15

PMID 38222731

Authors

Fatemeh Piri

Mahmoud Elahdadi Salmani

Hamid Sepehri

Affiliations

Soon will be listed here.

Abstract

Introduction: Autism spectrum disorder (ASD) is a disabling psychiatric disease characterized by impairments in communication and social skills. The pathophysiology of autism is complex and not fully known. Considering the incidence of sleep disorders in individuals with ASD and the important role of orexin in sleep, it is possible to hypothesize that an alteration of the orexinergic system could be implicated in the pathogenesis of autism symptoms. The present study was conducted to investigate the effect of suvorexant [dual orexin receptor antagonists (DORAs)] on autism-like behavior in prenatally valproic acid (VPA)-exposed rats].

Methods: Wistar female rats were administered VPA [600 mg/kg, intraperitoneally (i.p.)] or normal saline (10 ml/kg, i.p.; vehicle control) on gestational day 12.5. Thirty-two male offspring were divided into four groups: Control, VPA, Suvorexant+VPA, and VPA+Risperidone. The pups were given suvorexant [20 ml/kg, by mouth/orally (p.o.)] or risperidone (1 ml/kg, p.o.) daily from postnatal day (PND) (40-54). The offspring were tested for repetitive behaviors and cognitive ability with a Y-maze task on PND 55, and social interaction was assessed by play behavior in the open field on PND 56. And anxiety with using the three-chamber social assay on PND 56.

Results: In the Y-maze apparatus, spontaneous alteration significantly decreased in the prenatal VPA-treated rats compared to control rats showing autistic-like behavior, and 2-week suvorexant increased the alternation, indicating the beneficial effect of suvorexant. Prenatal treatment with VPA, impaired play behavior (sniffing, grooming, and darting), and increased anxiety-related behavior. Suvorexant treatment attenuated the problems in male offspring's social behavior.

Conclusion: Our results showed that suvorexant improved ASD-associated behaviors in the VPA-treated rats, and the orexinergic system may be associated with the pathogenesis of autism symptoms.

References

Nicolini C, Fahnestock M . The valproic acid-induced rodent model of autism. Exp Neurol. 2017; 299(Pt A):217-227. DOI: 10.1016/j.expneurol.2017.04.017. View

Ma N, Wang S, Sun Y, Ren J, Guo F . [Diagnostic value of contrast-enhanced ultrasound for accessory renal artery among patients suspected of renal artery stenosis]. Zhonghua Yi Xue Za Zhi. 2019; 99(11):838-840. DOI: 10.3760/cma.j.issn.0376-2491.2019.11.008. View

Dobrek L . An Outline of Renal Artery Stenosis Pathophysiology-A Narrative Review. Life (Basel). 2021; 11(3). PMC: 8000991. DOI: 10.3390/life11030208. View

. Correction and Republication: Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR Morb Mortal Wkly Rep. 2018; 67(45):1279. PMC: 6290808. DOI: 10.15585/mmwr.mm6745a7. View

Bayer L, Eggermann E, Saint-Mleux B, Machard D, Jones B, Muhlethaler M . Selective action of orexin (hypocretin) on nonspecific thalamocortical projection neurons. J Neurosci. 2002; 22(18):7835-9. PMC: 6758075. View

Favre M, Barkat T, Lamendola D, Khazen G, Markram H, Markram K . General developmental health in the VPA-rat model of autism. Front Behav Neurosci. 2013; 7:88. PMC: 3721005. DOI: 10.3389/fnbeh.2013.00088. View

Gilbert R, Al-Janabi A, Tomkins-Netzer O, Lightman S . Statins as anti-inflammatory agents: A potential therapeutic role in sight-threatening non-infectious uveitis. Porto Biomed J. 2020; 2(2):33-39. PMC: 6806973. DOI: 10.1016/j.pbj.2017.01.006. View

Krysiak R, Gdula-Dymek A, Okopien B . Effect of simvastatin and fenofibrate on cytokine release and systemic inflammation in type 2 diabetes mellitus with mixed dyslipidemia. Am J Cardiol. 2011; 107(7):1010-1018.e1. DOI: 10.1016/j.amjcard.2010.11.023. View

Chen Q, De Lecea L, Hu Z, Gao D . The hypocretin/orexin system: an increasingly important role in neuropsychiatry. Med Res Rev. 2014; 35(1):152-97. DOI: 10.1002/med.21326. View

10.

Rainero I, Ostacoli L, Rubino E, Gallone S, Picci L, Fenoglio P . Association between major mood disorders and the hypocretin receptor 1 gene. J Affect Disord. 2010; 130(3):487-91. DOI: 10.1016/j.jad.2010.10.033. View

11.

Hirsch A, Haskal Z, Hertzer N, Bakal C, Creager M, Halperin J . ACC/AHA Guidelines for the Management of Patients with Peripheral Arterial Disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Associations for Vascular Surgery/Society for Vascular Surgery,.... J Vasc Interv Radiol. 2006; 17(9):1383-97. DOI: 10.1097/01.RVI.0000240426.53079.46. View

12.

Dudchenko P . An overview of the tasks used to test working memory in rodents. Neurosci Biobehav Rev. 2004; 28(7):699-709. DOI: 10.1016/j.neubiorev.2004.09.002. View

13.

Laorden M, Ferenczi S, Pinter-Kubler B, Gonzalez-Martin L, Lasheras M, Kovacs K . Hypothalamic orexin--a neurons are involved in the response of the brain stress system to morphine withdrawal. PLoS One. 2012; 7(5):e36871. PMC: 3348891. DOI: 10.1371/journal.pone.0036871. View

14.

Kobylinska L, Panaitescu A, Gabreanu G, Anghel C, Mihailescu I, Rad F . PLASMATIC LEVELS OF NEUROPEPTIDES, INCLUDING OXYTOCIN, IN CHILDREN WITH AUTISM SPECTRUM DISORDER, CORRELATE WITH THE DISORDER SEVERITY. Acta Endocrinol (Buchar). 2019; -5(1):16-24. PMC: 6535330. DOI: 10.4183/aeb.2019.16. View

15.

Lawrence A . Regulation of alcohol-seeking by orexin (hypocretin) neurons. Brain Res. 2009; 1314:124-9. DOI: 10.1016/j.brainres.2009.07.072. View

16.

Marotta R, Risoleo M, Messina G, Parisi L, Carotenuto M, Vetri L . The Neurochemistry of Autism. Brain Sci. 2020; 10(3). PMC: 7139720. DOI: 10.3390/brainsci10030163. View

17.

Staples L, Cornish J . The orexin-1 receptor antagonist SB-334867 attenuates anxiety in rats exposed to cat odor but not the elevated plus maze: an investigation of Trial 1 and Trial 2 effects. Horm Behav. 2014; 65(3):294-300. DOI: 10.1016/j.yhbeh.2013.12.014. View

18.

Equihua A, De la Herran-Arita A, Drucker-Colin R . Orexin receptor antagonists as therapeutic agents for insomnia. Front Pharmacol. 2014; 4:163. PMC: 3872321. DOI: 10.3389/fphar.2013.00163. View

19.

Govindaiah G, Cox C . Modulation of thalamic neuron excitability by orexins. Neuropharmacology. 2006; 51(3):414-25. DOI: 10.1016/j.neuropharm.2006.03.030. View

20.

Boutrel B, Cannella N, De Lecea L . The role of hypocretin in driving arousal and goal-oriented behaviors. Brain Res. 2009; 1314:103-11. PMC: 4307927. DOI: 10.1016/j.brainres.2009.11.054. View