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Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers

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Abstract

Rationale

Modafinil is a wakefulness-promoting drug which is likely to activate some wakefulness-promoting and/or inhibit sleep-promoting neurones in the brain. The locus coeruleus (LC) is a wakefulness-promoting noradrenergic nucleus whose activity can be “switched off” by the α2-adrenoceptor agonist clonidine, leading to sedative and sympatholytic effects.

Objective

The aim of the study is to compare the effects of single doses of modafinil and clonidine on arousal and autonomic functions in human volunteers.

Methods

Sixteen healthy male volunteers participated in four experimental sessions (modafinil 200 mg; clonidine 0.2 mg; modafinil 200 mg + clonidine 0.2 mg; placebo) at weekly intervals, according to a balanced double-blind protocol. Arousal [pupillary “fatigue waves” (PFW), critical flicker fusion frequency, self-ratings of alertness] and autonomic functions (pupil diameter, pupillary light and darkness reflex responses, blood pressure, heart rate, salivation) were recorded. Data were analyzed with ANOVA, with multiple comparisons.

Results

Clonidine reduced subjective alertness, pupil diameter, the initial velocity and amplitude of the darkness reflex response, systolic and diastolic blood pressure and salivation, prolonged the recovery time of the light reflex response and increased PFW. Modafinil reduced PFW, increased pupil diameter and the initial velocity of the darkness reflex response and tended to reduce the effect of clonidine on pupil diameter and PFW. Modafinil had no effect on non-pupillary autonomic functions.

Conclusions

Clonidine exerted sympatholytic and sedative effects, whereas modafinil had sympathomimetic and some alerting effects. Modafinil may activate noradrenergic neurones in the LC involved in arousal and pupillary control, without affecting extracoerulear noradrenergic neurones involved in cardiovascular and salivary regulation.

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References

  • Abduljawad KAJ, Langley RW, Bradshaw CM, Szabadi E (1997) Effects of clonidine and diazepam on the acoustic startle response and on its inhibition by ‘prepulses’ in man. J Psychopharmacol 11:29–34

    Article  PubMed  CAS  Google Scholar 

  • Abduljawad KAJ, Langley RW, Bradshaw CM, Szabadi E (2001) Effects of clonidine and diazepam on prepulse inhibition of the acoustic startle response and the N1/P2 auditory evoked potential in man. J Psychopharmacol 15:237–242

    PubMed  CAS  Google Scholar 

  • Adler CH, Caviness JN, Hentz JG, Lind M, Tiede J (2003) Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease. Mov Disord 18:287–293

    Article  PubMed  Google Scholar 

  • Akaoka H, Roussel B, Lin JS, Chouvet G, Jouvet M (1991) Effect of modafinil and amphetamine on the rat catecholaminergic neuron activity. Neurosci Lett 123:20–22

    Article  PubMed  CAS  Google Scholar 

  • Arya DK, Langley RW, Szabadi E (1997) Comparison of the effects of high ambient temperature and clonidine on autonomic functions in man. Naunyn-Schmiedeberg's Arch Pharmacol 355:376–383

    Article  CAS  Google Scholar 

  • Baranski JV, Pigeau R, Dinich P, Jacobs I (2004) Effects of modafinil on cognitive and meta-cognitive performance. Hum Psychopharmacol 19:323–332

    Article  PubMed  CAS  Google Scholar 

  • Bayer L, Eggermann E, Serafin M, Grivel J, Machard D, Muhlethaler M, Jones BE (2005) Opposite effects of noradrenaline and acetylcholine upon hypocretin/orexin versus melanin concentrating hormone neurons in rat hypothalamic slices. Neuroscience 130:807–811

    Article  PubMed  CAS  Google Scholar 

  • Berridge CW, Waterhouse BD (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Rev 42:33–84

    Article  PubMed  Google Scholar 

  • Bitsios P, Prettyman R, Szabadi E (1996) Changes in autonomic function with age: a study of pupillary kinetics in healthy young and old people. Age Aging 25:432–438

    Article  CAS  Google Scholar 

  • Bitsios P, Szabadi E, Bradshaw CM (1998) The effects of clonidine on the fear-inhibited light reflex. J Psychopharmacol 12:137–145

    Article  PubMed  CAS  Google Scholar 

  • Bitsios P, Szabadi E, Bradshaw CM (1999) Comparison of the effects of venlafaxine, paroxetine and desipramine on the pupillary light reflex in man. Psychopharmacology 143:286–292

    Article  PubMed  CAS  Google Scholar 

  • Bitsios P, Szabadi E, Bradshaw CM (2004) The fear-inhibited light reflex: importance of the anticipation of an aversive event. Int J Psychophysiol 52:87–95

    Article  PubMed  CAS  Google Scholar 

  • Bond AJ, Lader MH (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218

    Google Scholar 

  • Buguet A, Montmayeur A, Pigeau RA, Naitoh P (1995) Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleep. J Sleep Res 4:229–241

    PubMed  Google Scholar 

  • Caldwell JA Jr, Caldwell JL, Smythe NK III, Hall KK (2000) A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study. Psychopharmacology 150:172–182

    Google Scholar 

  • DeBattista C, Doghramji K, Menza MA, Rosenthal MH, Fieve RR, Modafinil in Depression Study Group (2003) Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry 4:1057–1064

    Article  Google Scholar 

  • DeSarro GB, Ascioti C, Froio F, Libri V, Nistico G (1987) Evidence that locus coeruleus is the site where clonidine and drugs acting at α1- and α2-adrenoceptors affect sleep and arousal mechanisms. Br J Pharmacol 90:675–685

    PubMed  CAS  Google Scholar 

  • Dollery C (1999) Therapeutic drugs, 2nd edn. Churchill Livingstone, Edinburgh

    Google Scholar 

  • Duteil J, Rambert FA, Pessonnier J, Hermant JF, Gombert R, Assous E (1990) Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals. Eur J Pharmacol 180:49–58

    Article  PubMed  CAS  Google Scholar 

  • Ellis CM, Monk C, Simmons A, Lemmens G, Williams SC, Brammer M, Bullmore E, Parkes JD (1999) Functional magnetic resonance imaging neuroactivation studies in normal subjects and subjects with the narcoleptic syndrome. Actions of modafinil. J Sleep Res 8:85–93

    Article  PubMed  CAS  Google Scholar 

  • Eriksson KS, Sergeeva O, Brown RE, Haas HL (2001) Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. Neuroscience 21:9273–9279

    PubMed  CAS  Google Scholar 

  • Foote L, Aston-Jones GS (1995) Pharmacology and physiology of central noradrenergic systems. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Raven Press, New York, pp 335–345

    Google Scholar 

  • Freeman C, Hou RH, Langley RW, Szabadi E, Bradshaw CM (2004) Central noradrenergic modulation of autonomic functions: comparison of modafinil and clonidine. J Psychopharmacol 18(Supplement to No 3):A62

    Google Scholar 

  • Fung SJ, Manzoni D, Chan JY, Pompeiano O, Barnes CD (1991) Locus coeruleus control of spinal motor output. Prog Brain Res 88:395–409

    Article  PubMed  CAS  Google Scholar 

  • Gallopin T, Luppi PH, Rambert FA, Frydman A, Fort P (2004) Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study. Sleep 27:19–25

    PubMed  Google Scholar 

  • Gilbey MP (1997) Fundamental aspects of the control of sympathetic preganglionic neuronal discharge. In: Jordan D (ed) Central nervous control of autonomic function. Harwood, Amsterdam, pp 1–28

    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 U S A 96:10911–10916

    Article  PubMed  CAS  Google Scholar 

  • Hauser RA, Wahba MN, Zesiewicz TA, McDowell Anderson W (2000) Modafinil treatment of pramipexole-associated somnolence. Mov Disord 15:1269–1271

    Article  PubMed  CAS  Google Scholar 

  • Heitmann J, Cassel W, Grote L, Bickel U, Hartlaub U, Penzel T, Peter J (1999) Does short-term treatment with modafinil affect blood pressure in patients with obstructive sleep apnea? Clin Pharmacol Ther 65:328–335

    Article  PubMed  CAS  Google Scholar 

  • Horvath TL, Peyron C, Diano S, Ivanov A, Aston-Jones G, Kilduff TS, van Den Pol AN (1999) Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol 415:145–159

    Article  PubMed  CAS  Google Scholar 

  • Hou YP, Manns ID, Jones BE (2002) Immunostaining of cholinergic pontomesencephalic neurons for alpha 1 versus alpha 2 adrenergic receptors suggests different sleep–wake state activities and roles. Neuroscience 114:517–521

    Article  PubMed  CAS  Google Scholar 

  • Huang Z, Qu W, Li W, Mochizuki T, Eguchi N, Watanable T, Urade Y, Hayaishi O (2001) Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci U S A 98:9965–9970

    Article  PubMed  CAS  Google Scholar 

  • Hungs M, Mignot E (2001) Hypocretin/orexin, sleep and narcolepsy. BioEssays 23:397–408

    Article  PubMed  CAS  Google Scholar 

  • Ivanenko A, Tauman R, Gozal D (2003) Modafinil in the treatment of excessive daytime sleepiness in children. Sleep Med 4:579–582

    Article  PubMed  Google Scholar 

  • Keating GL, Rye DB (2003) Where you least expect it: dopamine in the pons and modulation of sleep and REM-sleep. Sleep 26:788–789

    PubMed  Google Scholar 

  • Kilduff TS, Peyron C (2000) The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci 23:359–365

    Article  PubMed  CAS  Google Scholar 

  • Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE (2003) Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci 23:7–11

    PubMed  CAS  Google Scholar 

  • Larijani GE, Goldberg ME, Hojat M, Khaleghi B, Dunn JB, Marr AT (2004) Modafinil improves recovery after general anesthesia. Anesth Analg 98:976–981

    Article  PubMed  CAS  Google Scholar 

  • Larson MD, Talke PO (2001) Effect of dexmedetomidine, an alpha2-adrenoceptor agonist, on human pupillary reflexes during general anaesthesia. Br J Clin Pharmacol 51:27–33

    Article  PubMed  CAS  Google Scholar 

  • Lin JS, Roussel B, Akaoka H, Fort P, Debilly G, Jouvet M (1992) Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat. Brain Res 591:319–326

    Article  PubMed  CAS  Google Scholar 

  • Loewenfeld IE (1993) The pupil: anatomy, physiology, and clinical applications (volume I). Wayne State University Press, Detroit, MI

    Google Scholar 

  • Longmore J, Theofilopoulos N, Szabadi E, Bradshaw CM (1987) Modification of the pupillary light reflex by miotic and mydriatic drugs: application of model of functional interaction. Br J Pharmacol 23:610–611

    Google Scholar 

  • Lowenthal DT, Matzek KM, Macgregor TR (1988) Clinical pharmacokinetics of clonidine. Clin Pharmacokinet 14:287–310

    Article  PubMed  CAS  Google Scholar 

  • Lüdtke H, Wilhelm B, Adler M, Schaeffel F, Wilhelm H (1998) Mathematical procedures in data recording and processing of pupillary fatigue waves. Vis Res 38:2889–2896

    Article  PubMed  Google Scholar 

  • MacDonald JR, Hill JD, Tarnopolsky MA (2002) Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy. Neurology 59:1876–1880

    PubMed  CAS  Google Scholar 

  • Makris AP, Rush CR, Frederich RC, Kelly TH (2004) Wake-promoting agents with different mechanisms of action : comparison of effects of modafinil and amphetamine on food intake and cardiovascular activity. Appetite 42:185–195

    Article  PubMed  CAS  Google Scholar 

  • Marwaha J, Aghajanian GK (1982) Relative potencies of alpha-1 and alpha-2 antagonists in the locus coeruleus, dorsal raphe and dorsal lateral geniculate nuclei: an electrophysiological study. J Pharmacol Exp Ther 222:287–293

    PubMed  CAS  Google Scholar 

  • Mignot E, Nishino S, Guilleminault C, Dement WC (1994) Modafinil binds to the dopamine uptake carrier site with low affinity. Sleep 17:436–437

    PubMed  CAS  Google Scholar 

  • Moldofsky H, Broughton RJ, Hill JD (2000) A randomized trial of the long-term, continued efficacy and safety of modafinil in narcolepsy. Sleep Med 1:109–116

    Article  PubMed  Google Scholar 

  • Morley MJ, Bradshaw CM, Szabadi E (1991) Effects of clonidine and yohimbine on the pupillary light reflex and carbachol-evoked sweating in healthy volunteers. Br J Clin Pharmacol 31:99–101

    PubMed  CAS  Google Scholar 

  • Morris STW, Reid JL (1997) Moxonidine: a review. J Hum Hypertens 11:629–635

    Article  PubMed  CAS  Google Scholar 

  • Muzi M, Goff DR, Kampine JP, Roerig DL, Ebert TJ (1992) Clonidine reduces sympathetic activity but maintains baroreflex responses in normotensive humans. Anesthesiology 77:864–871

    Article  PubMed  CAS  Google Scholar 

  • Nelson LE, Guo TZ, Lu J, Saper CB, Franks NP, Maze M (2002) The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway. Nat Neurosci 5:979–984

    Article  PubMed  CAS  Google Scholar 

  • Nelson LE, Lu J, Guo T, Saper CB, Franks NP (2003) The α2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects. Anesthesiology 98:428–436

    Article  PubMed  CAS  Google Scholar 

  • Nieuwenhuys R (1985) Chemoarchitecture of the brain. Springer, Berlin Heidelberg New York

    Google Scholar 

  • Norris H (1971) The action of sedatives on brain stem oculomotor systems in man. Neuropharmacology 10:181–189

    Article  PubMed  CAS  Google Scholar 

  • Ohman A, Hamm A, Hugdahl K (2000) Cognition and the autonomic system. Orienting, anticipation and conditioning. In: Cacioppo JT, Tassinary LG, Bernston GB (eds) Handbook of psychopharmacology, 2nd edn. Cambridge University Press, Cambridge, pp 533–575

    Google Scholar 

  • Pace-Schott EF, Hobson JA (2002) The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci 3:591–605

    PubMed  CAS  Google Scholar 

  • Pack AI, Black JE, Schwartz JR, Matheson JK (2001) Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care Med 164:1675–1681

    PubMed  CAS  Google Scholar 

  • Panula P, Pirvola U, Auvinen S, Airaksinen MS (1989) Histamine-immunoreactive nerve fibers in the rat brain. Neuroscience 28:585–610

    Article  PubMed  CAS  Google Scholar 

  • Peck RE (1959) The SHP test—an aid in the detection and measurement of depression. Arch Gen Psychiatry 1:35–40

    PubMed  CAS  Google Scholar 

  • Phillips MA, Szabadi E, Bradshaw CM (2000a) Comparison of the effects of clonidine and yohimbine on spontaneous pupillary fluctuations in healthy human volunteers. Psychopharmacology 150:85–89

    Article  PubMed  CAS  Google Scholar 

  • Phillips MA, Szabadi E, Bradshaw CM (2000b) Comparison of the effects of clonidine and yohimbine on pupillary diameter at different illumination levels. Br J Clin Pharmacol 50:65–68

    Article  PubMed  CAS  Google Scholar 

  • Pigeau R, Naitoh P, Buguet A, McCann C, Baranski J, Taylor M, Thompson M, MacK II (1995) Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature. J Sleep Res 4:212–228

    PubMed  Google Scholar 

  • Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN (2002) Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 72:179–183

    Article  PubMed  CAS  Google Scholar 

  • Randall DC, Shneerson JM, Plaha KK, File SE (2003) Modafinil affects mood, but not cognitive function, in healthy young volunteers. Hum Psychopharmacol 18:163–173

    Article  PubMed  CAS  Google Scholar 

  • Randall DC, Fleck NL, Shneerson JM, File SE (2004) The cognitive-enhancing properties of modafinil are limited in non-sleep-deprived middle-aged volunteers. Pharmacol Biochem Behav 77:547–555

    Article  PubMed  CAS  Google Scholar 

  • Regunathan S, Reis DJ (1996) Imidazoline receptors and their endogenous ligands. Annu Rev Pharmacol Toxicol 36:511–544

    Article  PubMed  CAS  Google Scholar 

  • Reid JL (1981) The clinical pharmacology of clonidine and related central antihypertensive agents. Br J Clin Pharmacol 12:295–302

    PubMed  CAS  Google Scholar 

  • Robbins TW, Everitt BJ (1995) Arousal system and attention. In: Gazzaniga MS (ed) The cognitive neurosciences. MIT Press, Cambridge, MA, pp 703–720

    Google Scholar 

  • Robertson P, Hellriegel ET (2003) Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet 42:123–137

    Article  PubMed  CAS  Google Scholar 

  • Rosenthal MH, Bryant SL (2004) Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia. Clin Neuropharmacol 27:38–43

    Article  PubMed  CAS  Google Scholar 

  • Rush CR, Kelly TH, Hays LR, Baker RW, Wooten AF (2002) Acute behavioural effects of modafinil in drug abusers. Behav Pharmacol 13:105–115

    PubMed  CAS  Google Scholar 

  • Saletu B, Frey R, Krupka M, Anderer P, Grunberger J, Barbanoj MJ (1989) Differential effects of a new central adrenergic agonist modafinil and d-amphetamine on sleep and early morning behaviour in young healthy volunteers. Int J Clin Pharmacol Res 9:183–195

    PubMed  CAS  Google Scholar 

  • Saper CB, Scammell TE (2004) Modafinil: a drug in search of a mechanism. Sleep 27:11–12

    PubMed  Google Scholar 

  • Saper CB, Chou TC, Scammell TE (2001) The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 24:726–731

    Article  PubMed  CAS  Google Scholar 

  • Scammell TE, Estabrooke IV, McCarthy MT, Chemelli RM, Yanagisawa M, Miller MS, Saper CB (2000) Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci 20:8620–8628

    PubMed  CAS  Google Scholar 

  • Smith SA (1992) Pupil function: tests and disorders. In: Bannister SR, Mathias CJ (eds) Autonomic failure, 3rd edn. Oxford University Press, Oxford, pp 421–441

    Google Scholar 

  • Smith JM, Misiak H (1976) Critical flicker frequency (CFF) and psychotropic drugs in normal human subjects—a review. Psychopharmacology 47:175–182

    Article  CAS  Google Scholar 

  • Spyer KM (1992) Central nervous control of cardiovascular system. In: Bannister SR, Mathias CJ Autonomic failure, 3rd edn. Oxford University Press, Oxford, pp 54–78

    Google Scholar 

  • Stevens DR, Kuramasu A, Eriksson KS, Selbach O, Haas HL (2004) α2-Adrenergic receptor-mediated presynaptic inhibition of GABAergic IPSPs in rat histaminergic neurons. Neuropharmacology 46:1018–1022

    Article  PubMed  CAS  Google Scholar 

  • Stivalet P, Esquivie D, Barraud PA, Leifflen D, Raphel C (1998) Effects of modafinil on attentional processes during 60 hours of sleep deprivation. Hum Psychopharmacol 13:501–507

    Article  CAS  Google Scholar 

  • Sutcliffe JG, de Lecea L (2002) The hypocretins: setting the arousal threshold. Nat Rev Neurosci 3:339–349

    Article  PubMed  CAS  Google Scholar 

  • Szabadi E (1977) The influence of the baseline on the size of pharmacological responses: a theoretical model. Br J Pharmacol 61:492–493

    Google Scholar 

  • Szabadi E, Bradshaw CM (1996) Autonomic pharmacology of α2-adrenoceptors. J Psychopharmacol 10(Supplement 3):6–18

    CAS  Google Scholar 

  • Szabadi E, Bradshaw CM (2000) Mechanisms of action of reboxetine. Rev Contemp Pharmacother 11:267–282

    CAS  Google Scholar 

  • Szabadi E, Tavernor S (1999) Hypo- and hypersalivation induced by psychoactive drugs. CNS Drugs 11:449–466

    Article  CAS  Google Scholar 

  • Szabadi E, Langley RW, Bradshaw CM (2002) Comparison of single doses of noradrenergic drugs on pupillary fatigue waves in a patient with excessive daytime sleepiness. J Sleep Res 11(Suppl 1):220

    Google Scholar 

  • Tanabe M, Ono H, Fukuda H (1990) Spinal alpha 1- and alpha 2-adrenoceptors mediate facilitation and inhibition of spinal motor transmission, respectively. J Pharmacol 54:69–77

    CAS  Google Scholar 

  • Theofilopoulos N, Szabadi E, Bradshaw CM (1984) Comparison of the effects of ranitidine and thioridazine on psychomotor functions in healthy volunteers. Br J Clin Pharmacol 18:135–144

    PubMed  CAS  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

    PubMed  CAS  Google Scholar 

  • US Modafinil in Narcolepsy Multicenter Study Group (1998) Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol 43:88–97

    Article  Google Scholar 

  • van Zwieten PA (1975) Antihypertensive drugs with a central action. Prog Pharmacol 1:1–63

    Google Scholar 

  • Walsh JK, Randazzo AC, Stone KL, Schweitzer PK (2004) Modafinil improves alertness, vigilance, and executive function during simulated night shifts. Sleep 27:434–439

    PubMed  Google Scholar 

  • Webster L, Andrews M, Stoddard G (2003) Modafinil treatment of opioid-induced sedation. Pain Med 4:135–140

    Article  PubMed  Google Scholar 

  • Wesensten NJ, Belenky G, Kautz MA, Thorne DR, Reichardt RM, Balkin TJ (2002) Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine. Psychopharmacology 159:238–247

    Article  PubMed  CAS  Google Scholar 

  • Williams JT, Henderson G, Rorth RA (1985) Characterization of α2-adrenoceptors which increase potassium conductance in rat locus coeruleus neurones. Neuroscience 14:95–101

    Article  PubMed  CAS  Google Scholar 

  • Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM (2001) Dopaminergic role in stimulant-induced wakefulness. J Neurosci 21:1787–1794

    PubMed  CAS  Google Scholar 

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  1. Psychopharmacology Section, Division of Psychiatry, University of Nottingham, Room B109, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK

    R. H. Hou, C. Freeman, R. W. Langley, E. Szabadi & C. M. Bradshaw

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  1. R. H. Hou
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  2. C. Freeman
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Hou, R.H., Freeman, C., Langley, R.W. et al. Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers. Psychopharmacology 181, 537–549 (2005). https://doi.org/10.1007/s00213-005-0013-8

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