Ahmed M. Kamel, Hesham H. Mohammed, Nora E. Abdel-Hamid


This study aimed to shed light on the effect of eszopiclone (ESZ) administration once daily for 30 consecutive days at night time on some neurochemical, behavioral and hematological criteria. A total of 27 male Wister albino rats were assigned to one of three drug treatment groups, vehicle, Eszopiclone (3mg/kg) and (6mg/kg). After 30 days of Eszopiclone administration, the neurochemical analysis revealed a significant reduction in serotonin and glutamate (306.44 ng/ml, 4.33 nmol /μl, respectively) in 6mg/kg treated animals, furthermore dopamine levels were significantly higher in rats treated with Eszopiclone (3mg/kg or 6mg/kg) in compare to control group. Reduced glutathione, superoxide dismutase and catalase levels revealed a significant decrease (0.15 μmol /gm tissue, 25.24 μmol /gm tissue, 1.93 Unit/gmtissue, respectively), while the malondialdehyde levels (15.79 nmol /gm tissue) demonstrated a significant increase in animals treated with 6 mg of ezopiclone. Behavioral assessment was carried out 3 times throughout the study (once/2 weeks) by video recording. It was recorded in 5 tests, including open field, the hole-board, inclined plain, grip and tail suspension tests. There were no changes between the rats in 3 mg/kg of ezopiclone and those in the control group. The rats in 6 mg/kg of ezopiclone showed less response in all behavioral observations, with significant decreases in inclined plain angle (23.35), exploratory time (17 second) and exploratory frequency (2 frequencies) in compare to other groups. The results support the concept that the administration of eszpiclone more than 3 mg/kg may lead to the behavioral changes. There were no serious adverse events regarding hematological indices. It is concluded that eszopiclone administration causes an imbalance between different neurotransmitters in the cerebrum. A marked decrease in antioxidant scavenging capacity with a behavioral alteration in 6mg/kg treated animals. The maximum safe dose of eszopiclone was 3mg/kg and more than this dose could lead to a deleterious reactions as evidenced in this study. 

Key words: eszopiclone; neurotransmitters; behavior; hematology

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(1) Najib J. Eszopiclone, a nonbenzo-diazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia. Clin Ther 2006; 28: 491–516.

(2) Jia F, Goldstein P, Harrison N. The modulation of synaptic GABAA receptors in the thalamus by eszopiclone and zolpidem. Pharmacol Exp Ther 2009; 328: 1000–6.

(3) Pritchett D, Seeburg P. Gamma-aminobutyric acid A receptor alpha 5-subunit creates novel type II benzodiazepine receptor pharmacology. Neurochem 1990; 54: 1802–4.

(4) Wieland H, Luddens H. Four amino acid exchanges convert a diazepam-insensitive inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor. Med Chem 1994; 37: 4576–80.

(5) Hanson S, Czajkowski C. Structural mechanisms underlying benzodiazepine modulation of the GABA (A) receptors. Neurosci 2008; 28: 3490–99.

(6) Meltzer L, Serpa K. Assessment of hypnotic effects in the rat: influence of the sleep-wake cycle. Drug Dev Res 1988; 14: 151–9.

(7) Edgar D, Seidel W, Dement W. Triazolam-induced sleep in the rats: influence of prior sleep, circadian time, and light/dark cycles. Psycopharmacol (Berl) 1991; 105: 374–80.

(8) Morin A. Strategies for treating chronic insomnia. Am Manag Care 2006; 12: S230–45.

(9) Ramakrishnan K, Scheid D. Treatment options for insomnia. Am Fam Physician 2007; 76: 517–26.

(10) Benavides J, Peny B, Durand A, Arbilla S, Scatton B. Comparative in-vivo and in-vitro regional selectivity of central omega (benzodiazepine) site ligands in inhibiting [3H] flumazenil binding in the rat central nervous system. Pharmacol Exp Ther 1992; 263: 884–96.

(11) Graham D, Faure C, Besnard F, Langer S. Pharmacological profile of benzodiazepine site ligands with recombinant GABAA receptor subtypes. Eur Neuropsychopharmacol 1996; 6: 119–25.

(12) Datta S, Siwek D. Single cell activity patterns of pedunculopentine tegumentum neurons across the sleep-wake cycle in the freely moving rats. Neurosci Res 2002; 70: 611–21.

(13) Rudolph U, Mohler H. GABA-based therapeutic approaches: GABAA receptor subtype functions. Curr Opin Pharmacol 2006; 6: 18–23.

(14) Steriade M, Timofee V. Neuronal plasticity in thalamocortical networks during sleep and walking oscillations. Neuron 2003; 37: 563–76.

(15) Mohammed H, Enas N, Shereen E. Impact of different litter materials on behaviour, growth performance, feet health and plumage score of Japanese quail (Coturnix japonica). Europ Poult Sci 2017; 81: 719–27.

(16) Walsh R, Cummim R. The open-field test A critical review. Psvcholoeical Bulletin 1976; 83: 482–504.

(17) Igarashi E, Takeshita S. Effects of illumination and handling upon rat open field activity. Physiol Behav 1995; 57(4): 699–703.

(18) Ramos A, Olivier B, Pierre M, Francis C. A multiple-test study of anxiety-related behaviours in six inbred rat strains. Behav Brain Res 1997; 85(1): 57–69.

(19) Chen P, Lee W, Sun W, Oyang Y, Fuh J. Risk of dementia in patients with insomnia and long-term use of hypnotics: a population-based retrospective cohort study. PLoS One 2012; 7(11): e49113.

(20) Kripke D, Langer R, Kline L. Hypnotics association with mortality or cancer: a matched cohort study. BMJ Open 2012; 2(1): e000850.

(21) Lin F, Chen P, Liao C, Hsieh Y, Sung F. Retrospective population cohort study on hip fracture associated with zolpidem medication. Sleep 2014; 37(4): 673–79.

(22) Lai M, Lin C, Liu C, Li T, Kao C. Long-term use of zolpidem increases the risk of major injury: a population-based cohort study. Mayo Clin Proc 2014; 89(5): 589–94.

(23) Qaseem A, Kansagara D, Forcia M, Cooke M, Denberg T. Clinical Guidelines Committee of the American College of Physicians. Management of chronic insomnia disorder in adults: a clinical practice guideline. Ann Intern Med 2016; 165: 125–33.

(24) Ford D, Kamerow D. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA 1989; 262: 1479–84.

(25) Johnson E, Roth T, Breslau N. The association of insomnia with anxiety disorders and depression: exploration of the direction of risk. Psychiatric Res 2006; 40: 700–8.

(26) Huang M, Radadia K, Macone B, Auerbach S, Data S. Effects of eszopiclone and zolpidem on sleep-wake behavior, anxiety-like behavior and contextual memory in rats. Behav Brain Res 2010; 210: 54–6.

(27) Coccheto D, Bjornsson T. Methods for vascular access and collection of body fluids from the laboratory rat. Pharm Sci 1993; 72: 465–92.

(28) Shyamjith M, Deepa B, Melinda S, Anu E, Roysten C. Assessment of brain dopamine levels to evaluate the role of Tylophora indica ethanolic extract on alcohol induced anxiety in Wister albino rats. Young Pharm 2016; 8(2): 91–5.

(29) Schlumfjf M, Lichtensteiger W, Langemann H, Waser P, Hefti F. A fluorometric micromethod for the simultaneous determination of serotonin, noradrenaline dopamine in milligram amounts in brain tissue. Biochem Pharmacol 1974; 23: 2337–46.

(30) Raju T, Kutty B, Sathyaprabha T, Shankarnarayana B. Brain and Behavior, National Institute of Mental Health and Neurosciences. Bangalore 2004; 134–8.

(31) Davies M, Brit D, Schnell R. Direct enzymatic assay for reduced and oxidized glutathione. Pharmacol Methods 1984; 12(3): 191–4.

(32) Ohkawa H, Ohisi N, Yagi K. Assay for lipid peroxides in animal tissue by thiobarbituric acid reaction. Anal Biochem 1979; 95: 351–8.

(33) Dacie J, Lewis S. Practical Hematology. 6th Ed., ELBS and Churchill Livingstone, London, UK 1984.

(34) Wintrobe M. Clinical Hematology 6th Ed., Lea and Febiger, Philadelphia 1967.

(35) Darcourt G, Pringuey D, Salliere D, Lavoisy J. The safety and tolerability of zolpidem; an update. Psycopharmacol 1999; 13(1): 81–93.

(36) Contó M, De Carvalho J, Benedito M. Behavioral differences between subgroups of rats with high and low threshold to clonic convulsions induced by DMCM, a benzodiazepine inverse agonist. Pharmacol Biochem Behav 2005; 82(3): 417–26.

(37) Godinho A, Trombini T, Oliveira E. Effects of elevated calcium on motor and exploratory activities of rats. Braz Med Biol Res 2002; 35(4): 451–7.

(38) Abou-Donia M, Dechkovskaia A, Goldstein L, Abdel-Rahman A, Bullman S, Khan W. Co-exposure to pyridostigmine bromide, DEET, and/or permethrin causes sensorimotor deficit and alterations in brain acetylcholinesterase activity. Pharmacol Biochemi Behav 2004; 77: 253–62.

(39) Andersen C, Andersen A, Finger S. Neurological correlates of unilateral and bilateral “strokes” of the middle cerebral artery in the rat. Physiol Behav 1991; 50: 263–9.

(40) Huwiler A. Tail suspension test. In: editor. Drug Discovery and Evaluation: Pharmacological Assays. 3rd ed. Vol. 1. New York 2008; 791–3.

(41) SAS. SAS statistical system Package-Jmp 8 User’s Guide. Second Edition. Cary, NC, SAS Institute Inc. USA. ISBN 978-1-60764-301-2, 2009.

(42) Krystal A, Walsh J, Laska E, Caron J, Amato D, Wessel T, Roth T. Sustained efficacy of eszopiclone over 6 months of nightly treatment; results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003; 26: 793–9.

(43) Buxton O, Pavlova M, O'Connor S, Wang W, Winkelman J. Lack of change in glucose metabolism in eszopiclone-treated primary insomnia patients. Nat Sci Sleep 2017; 9: 187–98.

(44) Winsky R. Role of GABAA receptors in the physiology and pharmacology of sleep. Eur Neurosci 2009; 29(9): 1779–94.

(45) Kumar S, Alam M, Bashir T, McGinty D, Szymusiak R. Central nervous system sites of sleep promoting effects of eszopiclone in rats. Neurosci 2011; 181: 67–78.

(46) Russell W, Daniel M, Jessica J, Meredith L, Kimberly N, Szebeni K, Attila S, Michelle D, Michelle C, Gregory A. Eszopiclone facilitation of the antidepressant activity of fluoxetine using a social defeat stress model. Pharmacol Biochem Behav 2011; 99(4): 648–58.

(47) Vaswani M, Linda F, Ramesh S. Role of selective serotonin reuptake inhibitors on psychiatric disorders. A comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27(1): 85–102.

(48) Ansorge M, Zhou M, Lira A, Hen R, Gingrich J. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 2004; 306: 879–81.

(49) Rothman RB, Blough BE, Baumann MH. Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions. AAPSJ 2007; 9(1):E1-E10.

(50) Monti J, Jantos H. The roles of dopamine and serotonin, and of their receptors in regulating sleep and waking. Prog Brain Res 2008; 172: 625–46.

(51) McEntee W, Crook T. Glutamate: its role in learning, memory and the aging brain. Psychopharmacology (Berl) 1993; 111(4): 391–401.

(52) European Medicines Agency. Withdrawal Assissment Reort for Lunivia International Nonproprietary Name: eszopiclone. 2009.

(53) Szebeni A, Szebeni K, Diperi TP, Johnson LA, Stockmeier CA, Crawford JD, Chandley MJ, Hernandez LJ, Burgess KC, Brown RW, Ordway GA. Elevated DNA oxidation and DNA repair enzyme expression in brain white matter in major depressive disorder. Int Neuropsychopharmacol 2017; 20(5):363-73.

(54) Kalogiannis M, Delikatny J, Jeitner T. Serotonin as a putative scavenger of hypohalous acid in the brain. Biochem Biophys Acta 2016; 1862: 651–61.

(55) Lovett B, Watts D, Grossman M. Prolonged coma after eszopiclone overdose. Am Emer Med 2007; 25(6): 375.e5–6.

(56) Khalil S, Awad A, Mohammed H, Nasaan M. Imidacloprid insecticide exposure induces stress and disrupts glucose homeostasis in male rats. Environ Toxicol Pharmacol 2017; 55: 165–74.

(57) Fukushiro D, Carvalho R, Ricardo V, Alvarez J, Ribeiro L, Frussa-Filho R. Haloperidol (but not ziprasidone) withdrawal potentiates sensitization to the hyperlocomotor effect of cocaine in mice. Brain Res Bull 2008; 77(2-3): 124–8.

(58) Patti C, Frussa-Filho R, Silva R, Carvalho R, Kameda S, Takatsu-Coleman A, Cunha J, Abílio V. Behavioral characterization of morphine effects on motor activity in mice. Pharmacol Biochem Behav 2005; 81(4): 923–7.

(59) Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur Pharmacol 2003; 463(1-3): 3–33.

(60) Cenk T, Laura B, Andrew D, Vinod H, Pamela C, Erin L, Sinan G. The impact of eszopiclone on sleep and congnition in patients with schizophrenia and insomnia: A double-blind, randomized, placebo-controlled trial. Schizophrenia Research 2014; 160: 180–5.

(61) Khalil S, Khalifa H, Sabry M, Mohammed H, Elewa Y, Hend A. Spirulina platensis attenuates the associated neurobehavioral and inflammatory response impairments in rats exposed to lead acetate. Environ Toxicol Pharmacol 2018; 157: 255–65.

(62) Nutt D. Relationship of neurotransmitters to the symptoms of major depressive disorder. Clin Psychiatry 2008; 69: 4–7.



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