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Wake-promoting agent modafinil worsened attentional performance following REM sleep deprivation in a young-adult rat model of 5-choice serial reaction time task

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Abstract

Rationale

Individuals who experience sleep loss may exhibit certain physiological abnormalities. Central stimulant drugs have been studied in sleep-loss conditions, and some of them might be therapeutically beneficial. Modafinil (diphenyl-methyl-sulfinyl-2-acetamide, MOD) has been increasingly employed for elevating alertness and vigilance in recent years, yet the underlying mechanism of actions for MOD is not fully understood.

Objectives

To examine the behavioral effect of MOD following rapid eye movement sleep deprivation (REMD) in rats. A five-choice serial reaction time task (5-CSRTT) was employed to investigate animals’ attentional performance and impulsive reactivity.

Materials and methods

Rats of different ages were trained to learn the 5-CSRTT. REMD with the water platform method was applied for 96 h. The impacts of REMD on 5-CSRTT in middle-age (32-weeks-old) and young-adult (12-week-old) rats were compared with baseline or a condition with shorter visual stimulus duration.

Results

The results revealed that following REMD, young-adult but not middle-age rats were liable to be affected in their performances of the 5-CSRTT. In young-adult rats, while MOD had no contributions to the effect of REMD, it worsened rats’ performance following REMD when the stimulus duration was shortened, as shown by the reduced number of correct responses and prolonged magazine latency.

Conclusions

These results suggest that aging might be a crucial factor for the physiological impact following REMD. MOD should be used cautiously, particularly, in conditions that require REM sleep.

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References

  • Adriani W, Laviola G (2003) Elevated levels of impulsivity and reduced place conditioning with d-amphetamine: two behavioral features of adolescence in mice. Behav Neurosci 117:695–703

    Article  CAS  PubMed  Google Scholar 

  • Anderson KJ, Revelle W, Lynch MJ (1989) Caffeine, impulsivity, and memory scanning: a comparison of two explanations for the Yerkes–Dodson effect. Motiv Emot 13:1–20

    Article  Google Scholar 

  • Bastuji H, Jouvet M (1988) Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog Neuro-psychopharmacol Biol Psychiatry 12:695–700

    Article  CAS  Google Scholar 

  • Beaulieu-Bonneau S, Hudon C (2009) Sleep disturbances in older adults with mild cognitive impairment. Int Psychogeriatr 21:654–666

    Article  PubMed  Google Scholar 

  • Borbely AA (1989) Sleep homeostasis and models of sleep regulation. In: Kryger M, Roth T, Dement WC (eds) Principles and practice of sleep medicine. Saunders, Philadelphia, pp 309–320

    Google Scholar 

  • Bourgin P, Huitrón-Résendiz S, Spier AD, Fabre V, Morte B, Criado JR, Sutcliffe JG, Henriksen SJ, de Lecea L (2000) Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 20:7760–7765

    CAS  PubMed  Google Scholar 

  • Bushnell PJ (1998) Behavioral approaches to the assessment of attention in animals. Psychopharmacology 138:231–259

    Article  CAS  PubMed  Google Scholar 

  • Caldwell JA, Caldwell JL (1997) An in-flight investigation of the efficacy of dextroamphetamine for sustaining helicopter pilot performance. Aviat Space Environ Med 68:1073–1080

    CAS  PubMed  Google Scholar 

  • Caldwell JA, Caldwell JL (2005) Fatigue in military aviation: an overview of US military-approved pharmacological countermeasures. Aviat Space Environ Med 76:39–51

    Google Scholar 

  • Chapotot F, Pigeau R, Canini F, Bourdon L, Buguet A (2003) Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG. Psychopharmacology 166:127–138

    CAS  PubMed  Google Scholar 

  • Christie MA, McKenna JT, Connolly NP, McCarley RW, Strecker RE (2008) 24 h of sleep deprivation in the rat increases sleepiness and decreases vigilance: introduction of the rat-psychomotor vigilance task. J Sleep Res 17:376–384

    Article  PubMed  Google Scholar 

  • Cirulli F, Laviola G (2000) Paradoxical effects of d-amphetamine in infant and adolescent mice: role of gender and environmental risk factors. Neurosci Biobehav Rev 24:73–84

    Article  CAS  PubMed  Google Scholar 

  • Cole BJ, Robbins TW (1989) Effects of 6-hydroxydopamine lesions of the Nucleus accumbens septi on performance of a 5-choice serial reaction time task in rats: implications for theories of selective attention and arousal. Behav Brain Res 33:165–179

    Article  CAS  PubMed  Google Scholar 

  • Córdova CA, Said BO, McCarley RW, Baxter MG, Chiba AA, Strecker RE (2006) Sleep deprivation in rats produces attentional impairments on a 5-choice serial reaction time task. Sleep 29:69–76

    PubMed  Google Scholar 

  • Czeisler CA, Duffy JF, Shanahan TL et al (1999) Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 284:2177–2181

    Article  CAS  PubMed  Google Scholar 

  • Czeisler CA, Walsh JK, Roth T et al (2005) Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J Med 353:476–486

    Article  CAS  PubMed  Google Scholar 

  • Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O’Brien CP (2005) A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology 30:205–211

    Article  CAS  PubMed  Google Scholar 

  • Dahl RE (1996) The impact of inadequate sleep on children’s daytime cognitive function. Semin Pediatr Neurol 3:44–50

    Article  CAS  PubMed  Google Scholar 

  • Dalley JW, Cardinal RN, Robbins TW (2004) Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 28:771–784

    Article  CAS  PubMed  Google Scholar 

  • Dalley JW, Theobald DE, Berry D, Milstein JA, Lääne K, Everitt BJ, Robbins TW (2005) Cognitive sequelae of intravenous amphetamine self-administration in rats: evidence for selective effects on attentional performance. Neuropsychopharmacology 30:525–537

    Article  CAS  PubMed  Google Scholar 

  • Didato G, Nobili L (2009) Treatment of narcolepsy. Expert Rev Neurother 9:897–910

    Article  CAS  PubMed  Google Scholar 

  • Eagle DM, Tufft MR, Goodchild HL, Robbins TW (2007) Differential effects of modafinil and methylphenidate on stop-signal reaction time task performance in the rat, and interactions with the dopamine receptor antagonist cis-flupenthixol. Psychopharmacology 192:193–206

    Article  CAS  PubMed  Google Scholar 

  • Eliyahu U, Berlin S, Hadad E, Heled Y, Moran DS (2007) Psychostimulants and military operations. Mil Med 172:383–387

    PubMed  Google Scholar 

  • Espiritu JR (2008) Aging-related sleep changes. Clin Geriatr Med 24:1–14

    Article  PubMed  Google Scholar 

  • Evenden JL (1999) Varieties of impulsivity. Psychopharmacology 146:348–361

    Article  CAS  PubMed  Google Scholar 

  • Ferraz MR, Ferraz MM, Santos R (2001) How REM sleep deprivation and amantadine affects male rat sexual behavior. Pharmacol Biochem Behav 69:325–332

    Article  CAS  PubMed  Google Scholar 

  • Frisone DF, Frye CA, Zimmerberg B (2002) Social isolation stress during the third week of life has age-dependent effects on spatial learning in rats. Behav Brain Res 128:153–160

    Article  PubMed  Google Scholar 

  • Fuxe K, Janson AM, Rosén L, Finnman UB, Tanganelli S, Morari M, Goldstein M, Agnati LF (1992) Evidence for a protective action of the vigilance promoting drug modafinil on the MPTP-induced degeneration of the nigrostriatal dopamine neurons in the black mouse: an immunocytochemical and biochemical analysis. Exp Brain Res 88:117–130

    Article  CAS  PubMed  Google Scholar 

  • Godoi FR, Oliveira MG, Tufik S (2005) Effects of paradoxical sleep deprivation on the performance of rats in a model of visual attention. Behav Brain Res 165:138–145

    Article  PubMed  Google Scholar 

  • Goetghebeur P, Dias R (2009) Comparison of haloperidol, risperidone, sertindole, and modafinil to reverse an attentional set-shifting impairment following subchronic PCP administration in the rat — a back translational study. Psychopharmacology 202:287–293

    Article  CAS  PubMed  Google Scholar 

  • Greco B, Carli M (2006) Reduced attention and increased impulsivity in mice lacking NPY Y2 receptors: relation to anxiolytic-like phenotype. Behav Brain Res 169:325–334

    Article  CAS  PubMed  Google Scholar 

  • Greenberg R, Pillard R, Pearlman C (1972) The effect of dream (stage REM) deprivation on adaptation to stress. Psychosom Med 34:257–262

    CAS  PubMed  Google Scholar 

  • Greene R, Siegel J (2004) Sleep: a functional enigma. NeuroMol Med 5:59–68

    Article  CAS  Google Scholar 

  • Grottick AJ, Higgins GA (2002) Assessing a vigilance decrement in aged rats: effects of pre-feeding, task manipulation, and psychostimulants. Psychopharmacology 164:33–41

    Article  CAS  PubMed  Google Scholar 

  • Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S, Benham CD, Taylor SG, Routledge C, Hemmati P, Munton RP, Ashmeade TE, Shah AS, Hatcher JP, Hatcher PD, Jones DN, Smith MI, Piper DC, Hunter AJ, Porter RA, Upton N (1999) Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci 96:10911–109116

    Article  CAS  PubMed  Google Scholar 

  • Howell LL, Kimmel HL (2008) Monoamine transporters and psychostimulant addiction. Biochem Pharmacol 75:196–217

    Article  CAS  PubMed  Google Scholar 

  • John J, Wu MF, Boehmer LN, Siegel JM (2004) Cataplexy-active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron 42:619–634

    Article  CAS  PubMed  Google Scholar 

  • Karila L, Gorelick D, Weinstein A et al (2008) New treatments for cocaine dependence: a focused review. Int J Neuropsychopharmacol 11:425–438

    Article  CAS  PubMed  Google Scholar 

  • Kavushansky A, Vouimba RM, Cohen H, Richter-Levin G (2006) Activity and plasticity in the CA1, the dentate gyrus, and the amygdala following controllable vs. uncontrollable water stress. Hippocampus 16:35–42

    Article  PubMed  Google Scholar 

  • Killgore WD, Kahn-Greene ET, Grugle NL, Killgore DB, Balkin TJ (2009) Sustaining executive functions during sleep deprivation: a comparison of caffeine, dextroamphetamine, and modafinil. Sleep 32:205–216

    PubMed  Google Scholar 

  • Kushida CA (2006) Countermeasures for sleep loss and deprivation. Curr Treat Options Neurol 8:361–366

    Article  PubMed  Google Scholar 

  • Liu YP, Lin YL, Chuang CH, Kao YC, Chang ST, Tung CS (2009) Alpha adrenergic modulation on effects of norepinephrine transporter inhibitor reboxetine in five-choice serial reaction time task. J Biomed Sci 16:72–83

    Article  PubMed  Google Scholar 

  • Maitra KK, Dasgupta AK (2005) Incoordination of a sequential motor task in Parkinson’s disease. Occup Ther Int 12:218–233

    Article  PubMed  Google Scholar 

  • Martínez-Raga J, Knecht C, Cepeda S (2008) Modafinil: a useful medication for cocaine addiction? Review of the evidence from neuropharmacological, experimental and clinical studies. Curr Drug Abuse Rev 1:213–221

    Article  PubMed  Google Scholar 

  • Martins RC, Andersen ML, Shih MC, Tufik S (2008) Effects of cocaine, methamphetamine and modafinil challenge on sleep rebound after paradoxical sleep deprivation in rats. Braz J Med Biol Res 41:68–77

    CAS  PubMed  Google Scholar 

  • Mendelson WB, Bergmann BM (2000) Age-dependent changes in recovery sleep after 48 hours of sleep deprivation in rats. Neurobiol Aging 21:689–693

    Article  CAS  PubMed  Google Scholar 

  • Milstein JA, Dalley JW, Theobald DEH, Robbins TW (2003) Effect of modafinil on performance of the 5-choice serial reaction time task in rats. J Psychopharmacol 17:G45

    Google Scholar 

  • Morgan RE, Crowley JM, Smith RH, LaRoche RB, Dopheide MM (2007) Modafinil improves attention, inhibitory control, and reaction time in healthy, middle-aged rats. Pharmacol Biochem Behav 86:531–541

    Article  CAS  PubMed  Google Scholar 

  • Münch M, Knoblauch V, Blatter K et al (2004) The frontal predominance in human EEG delta activity after sleep loss decreases with age. Eur J Neurosci 20:1402–1410

    Article  PubMed  Google Scholar 

  • Orzeł-Gryglewska J (2010) Consequences of sleep deprivation. Int J Occup Med Environ Health 23:95–114

    Article  PubMed  Google Scholar 

  • Pokk P, Väli M (2001) Small platform stress increases exploratory activity of mice in staircase test. Prog Neuropsychopharmacol Biol Psychiatry 25:1435–1444

    Article  CAS  PubMed  Google Scholar 

  • Porkka-Heiskanen T, Smith SE, Taira T, Urban JH, Levine JE, Turek FW, Stenberg D (1995) Noradrenergic activity in rat brain during rapid eye movement sleep deprivation and rebound sleep. Am J Physiol 268:1456–1463

    Google Scholar 

  • Robbins TW (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology 163:362–380

    Article  CAS  PubMed  Google Scholar 

  • Shaffery JP, Oksenberg A, Marks GA, Speciale SG, Mihailoff G, Roffwarg HP (1998) REM sleep deprivation in monocularly occluded kittens reduces the size of cells in LGN monocular segment. Sleep 21:837–845

    CAS  PubMed  Google Scholar 

  • Shearer J (2008) The principles of agonist pharmacotherapy for psychostimulant dependence. Drug Alcohol Rev 27:301–308

    Article  PubMed  Google Scholar 

  • Shiromani PJ, Lu J, Wagner D et al (2000) Compensatory sleep response to 12 h wakefulness in young and old rats. Am J Physiol Regul Integr Comp Physiol 278:125–133

    Google Scholar 

  • Soubrie P (1986) Reconciling the role of central serotonin neurons in human and animal behaviour. Behav Brain Sci 9:314–364

    Google Scholar 

  • Theunissen EL, Elvira Jde L, van den Bergh D, Ramaekers JG (2009) Comparing the stimulant effects of the H1-antagonist fexofenadine with 2 psychostimulants, modafinil and methylphenidate. J Clin Psychopharmacol 29:439–443

    Article  CAS  PubMed  Google Scholar 

  • Touret M, Sallanon-Moulin M, Jouvet M (1995) Awakening properties of modafinil without paradoxical sleep rebound: comparative study with amphetamine in the rat. Neurosci Lett 189:43–46

    Article  CAS  PubMed  Google Scholar 

  • Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ (2003) Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology 165:260–269

    CAS  PubMed  Google Scholar 

  • Turner DC, Clark L, Dowson J, Robbins TW, Sahakian BJ (2004) Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biol Psychiatry 55:1031–1040

    Article  CAS  PubMed  Google Scholar 

  • van Someren EJ (2000) More than a marker: interaction between the circadian regulation of temperature and sleep, age-related changes, and treatment possibilities. Chronobiol Int 17:313–354

    Article  PubMed  Google Scholar 

  • van Vliet SA, Jongsma MJ, Vanwersch RA, Olivier B, Philippens IH (2008) Efficacy of caffeine and modafinil in counteracting sleep deprivation in the marmoset monkey. Psychopharmacology 197:59–66

    Article  CAS  PubMed  Google Scholar 

  • Velazquez-Moctezuma J, Dominguez-Salazar E, Cortes-Barberena E et al (2004) Differential effects of rapid eye movement sleep deprivation and immobilization stress on blood lymphocyte subsets in rats. Neuroimmunomodulation 11:261–267

    Article  CAS  PubMed  Google Scholar 

  • Waters KA, Burnham KE, O’connor D, Dawson GR, Dias R (2005) Assessment of modafinil on attentional processes in a five-choice serial reaction time test in the rat. J Psychopharmacol 19:149–158

    Article  CAS  PubMed  Google Scholar 

  • Wojcik WJ, Radulovacki M (1981) Selective increase in brain dopamine metabolism during REM sleep rebound in the rat. Physiol Behav 27:305–312

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the National Science Council (NSC 96-2314-B-073-001) of the Taiwanese government and a grant of the National Defense Medical Center (DOD 95-04-03) at Taipei, Taiwan, ROC. Special thanks goes to Prof. An-Rong Lee at School of Pharmacy, National Defense Medical Center, for the synthetic work of MOD. Declaration: all experiments comply with the current laws of Taiwan.

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Liu, YP., Tung, CS., Lin, YL. et al. Wake-promoting agent modafinil worsened attentional performance following REM sleep deprivation in a young-adult rat model of 5-choice serial reaction time task. Psychopharmacology 213, 155–166 (2011). https://doi.org/10.1007/s00213-010-2019-0

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