The noradrenergic locus coeruleus is a major wakefulness-promoting nucleus of the brain, which is also involved in the regulation of autonomic and endocrine functions. The activity of the locus coeruleus is believed to be tonically enhanced by a mesocoerulear dopaminergic pathway arising from the ventral tegmental area of the midbrain. Both modafinil, a wakefulness-promoting drug, and pramipexole, a D2/D3receptor agonist with sedative properties, may act on this pathway, with modafinil increasing and pramipexole decreasing locus coeruleus activity. The aim of this study was to compare the two drugs on alertness, autonomic and endocrine functions in healthy volunteers. Pramipexole (0.5mg), modafinil (200mg), and their combination were administered to 16 healthy males in a double-blind, placebo-controlled design. Methods included tests of alertness (pupillographic sleepiness test, critical flicker fusion frequency, visual analogue scales), autonomic functions (resting pupil diameter, light and darkness reflex responses, heart rate, blood pressure, salivation, core temperature), and endocrine functions (blood concentrations of prolactin, growth hormone, and thyroid stimulating hormone). Data were analysed by ANOVA. Pramipexole reduced alertness, caused pupil dilatation, increased heart rate, reduced prolactin and thyroid stimulating hormone, and increased growth hormone level. Modafinil caused small increases in blood pressure and core temperature, and reduced prolactin levels. The sedative effect of pramipexole and the autonomic effects of modafinil are consistent with altered activity in the mesocoerulear pathway; the pupil dilatation following pramipexole suggests reduced dopaminergic excitation of the Edinger-Westphal nucleus.
Abduljawad K A J , Langley R W , Bradshaw C M , Szabadi E (1997) Effects of clonidine and diazepam on the acoustic startle response and on its inhibition by ‘prepulses’ in man . J Psychopharmacol11: 29–34 .
2.
Adler C H , Caviness J N , Hentz J G , Lind M , Tiede J (2003) Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease . Mov Disord18: 287–293 .
3.
Arya D K , Langley R W , Szabadi E , Bradshaw C M (1997) Comparison of the effects of high ambient temperature and clonidine on autonomic functions in man . Naunyn-Schmiedeberg's Arch Pharmacol355: 376–383 .
4.
Bagetta G , De Sarro G , Priolo E , Nistico G (1988) Ventral tegmental area: site through which dopamine D2-receptor agonists evoke behavioural and electrocortical sleep in rats . Br J Pharmacol95: 860–866 .
5.
Ben-Jonathan N , Hnasko R (2001) Dopamine as a prolactin (PRL) inhibitor . Endocr Rev22: 724–763 .
6.
Bond A J , Lader M H (1974) The use of analogue scales in rating subjective feelings . Br J Med Psychol47: 211–218 .
7.
Brun J , Chamba G , Khalfallah Y , Girard P , Boissy I , Bastuji H , Sassolas G , Claustrat B (1998) Effect of modafinil on plasma melatonin, cortisol and growth hormone rhythms, rectal temperature and performance in healthy subjects during a 36h sleep deprivation . J Sleep Res7: 105–114 .
8.
Caldwell J A Jr , Caldwell J L , Smythe N K , Hall K K (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 (Berl.) 150: 272–282 .
9.
DeBattista C , Doghramji K , Menza M A , Rosenthal M H , Fieve R R , 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 Psychiatry64: 1057–1064 .
10.
Ellis C M , Monk C , Simmons A , Lemmens G , Williams S C R , Brammer M , Bullmore E , Parkes J D (1999) Functional magnetic resonance imaging neuroactivation studies in normal subjects and subjects with the narcoleptic syndrome. Actions of modafinil . J Sleep Res8: 85–93 .
11.
Ferreira J J , Galitzky M , Thalamus C , Tiberge M , Montastruc J L , Sampaio C , Rascol O (2002) Effect of ropinirole on sleep onset: a randomised, placebo-controlled study in healthy volunteers . Neurology58: 460–460 .
12.
Guistina A , Veldhuis J D (1998) Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human . Endocr Rev19: 717–797 .
13.
Guyenet P G (1980) The coeruleospinal noradrenergic neurons: anatomical and electrophysiological studies in the rat . Brain Res189: 121–133 .
14.
Hancock M B , Fougerousse C L (1976) Spinal projections from the nucleus locus coeruleus and nucleus subcoeruleus in the cat and monkey as demonstrated by the retrograde transport of horseradish peroxidase . Brain Res Bull1: 229–234 .
15.
Hauser R A , Gauger L , McDowell Anderson W , Zesiewicz T A (2000a) Pramipexole-induced somnolence and episodes of daytime sleep . Mov Disord15: 658–663 .
16.
Hauser R A , Wahba M N , Zesiewicz T A , McDowell Anderson W (2000b) Modafinil treatment of pramipexole associated somnolence . Mov Disord15: 1269–1271 .
17.
Heitmann J , Cassel W , Grote L , Bickel U , Hartlaub U , Penzel T , Peter J H (1999) Does short-term treatment with modafinil affect blood pressure in patients with obstructive sleep apnea?Clin Pharmacol Ther65: 328–335 .
18.
Hou R H , Freeman C , Langley R W , Szabadi E , Bradshaw C M (2005) Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers . Psychopharmacology (Berl), 181: 537–549 .
19.
Howell D C (2002) Statistical Methods for Psychology, 5th edn.Duxbury, Pacific Grove, CA , p. 340–340.
20.
Ivanenko A , Tauman R , Gozal D (2003) Modafinil in the treatment of excessive daytime sleepiness in children . Sleep Med4: 579–582 .
21.
Kang Y-M , Ouyang W , Chen J-Y , Qiao J-T , Dafny N (2000) Norepinephrine modulates single hypothalamic arcuate neurons via 1 and adrenergic receptors . Brain Res869: 146–157 .
22.
Keating G L , Rye D B (2003) Where you least expect it: dopamine in the pons and modulation of sleep and REM-sleep . Sleep26: 788–789 .
23.
Lal S , Nair N P , Iskandar H L , Etienne P , Wood P L , Schwartz G , Guyda H (1975) Effect of domperidone on apomorphine-induced growth hormone secretion in normal men . J Neural Transm54: 75–84 .
24.
Loewenfeld I E (1993) The Pupil: Anatomy, Physiology, and Clinical Applications. Wayne State University Press, Detroit, MI .
25.
Lowenstein O , Feinbeig R , Lowenfeld I E (1963) Pupillary movements during acute and chronic fatigue . Invest Opthalmol2: 138–157 .
26.
Lüdtke H , Wilhelm B , Adler M , Schaeffel F , Wilhelm H (1998) Mathematical procedures in data recording and processing of pupillary fatigue waves . Vision Res38: 2889–2896 .
27.
MacDonald J R , Hill J D , Tarnopolsky M A (2002) Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy . Neurology59: 1876–1880 .
28.
Maeda T , Kitahama K , Geffard M (1994) Dopaminergic innervation of rat locus coeruleus: a light and electron microscope immunohistochemical study . Microsc Res Tech29: 211–218 .
29.
Makris A P , Rush C R , Frederich R C , Kelly T H (2004) Wake-promoting agents with different mechanisms of action: comparison of effects of modafinil and amphetamine on food intake and cardiovascular activity . Appetite42: 185–195 .
30.
Mansour A , Watson S J Jr (1995) Dopamine receptor expression in the central nervous system. In Bloom F E , Kupfer D J (eds), Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York , pp. 207–219.
31.
Mason G A , Garbutt J C , Prange A J Jr (1995) Thyrotropin-releasing hormone: focus on basic neurobiology. In Bloom F E , Kupfer D J (eds), Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York , pp. 493–504
32.
Mierau J (1995) Pramipexole: a dopamine-receptor agonist for treatment of Parkinson's disease . Clin Neuropharmacol18 (Suppl. 1): S195–S206 .
33.
Millan M J , Maiofiss L , Cussac D , Audinot V , Boutin J-A , Newman-Tancredi A (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes . J Pharmacol Exp Ther303: 791–804 .
34.
Moore K E , Lookingland K J (1995) Dopaminergic neuronal systems in the hypothalamus. In Bloom F E , Kupfer D J (eds), Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York , pp. 245–256.
35.
Müller E E , Locatelli V , Cocchi D (1999) Neuroendocrine control of growth hormone secretion . Physiol Rev79: 511–607 .
36.
Müller E E , Locatelli V , Ghigo E , Cella S G , Loche S , Pintor C , Camanni F (1991) Involvement of brain catecholamines and acetylcholine in growth hormone deficiency states: pathophysiological, diagnostic and therapeutic implications . Drugs41: 161–177 .
37.
Nieves A V , Lang A E (2002) Treatment of excessive daytime sleepiness in patients with Parkinson's disease with modafinil . Clinical Neuropharmacology25: 111–114 .
38.
Norris H (1971) The action of sedatives on brain stem oculomotor systems in man . Neuropharmacology10: 181–189
39.
O'Donohue T L , Crowley W R , Jacobowitz D M (1979) Biochemical mapping of the noradrenergic ventral bundle projection sites: evidence for a noradrenergic–dopaminergic interaction . Brain Res172: 87–100 .
40.
O'suilleabhain P E , Dewey R B (2002) Contributions of dopaminergic drugs and disease severity to daytime sleepiness in Parkinson's disease . Arch Neurol59: 986–989 .
41.
Ornstein K , Milon H , McRae-Degueurce A , Alvarez C , Berger B , Würzner H P (1987) Biochemical and radioautographic evidence for dopaminergic afferents of the locus coeruleus originating in the ventral tegmental area . J Neural Transm70: 183–191 .
42.
Pack A I , Black J E , Schwartz J R L , Matheson J K (2001) Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea . Am J Respir Crit Care Med164: 1675–1681 .
43.
Parkinson Study Group (1997) Safety and efficacy of pramipexole in early Parkinson disease: a randomized dose-ranging study . JAMA278: 125–130 .
44.
Parkinson Study Group (2000) Pramipexole vs. levodopa as initial treatment for Parkinson disease: a randomized controlled trial . JAMA284: 1931–1938 .
45.
Paus S , Brecht H M , Koster J , Seeger G , Klockgether T , Wullner U (2003) Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson's disease . Mov Disord18: 659–667 .
46.
Peck R E (1959) The SHP test – an aid in the detection and measurement of depression . Arch Gen Psychiatry1: 35–40 .
47.
Phillips M A , Szabadi E , Bradshaw C M (2000a) Comparison of the effects of clonidine and yohimbine on spontaneous pupillary fluctuations in healthy human volunteers . Psychopharmacology150: 85–89 .
48.
Phillips M A , Bitsios P , Szabadi E , Bradshaw C M (2000b) Comparison of the antidepressants reboxetine, fluvoxamine and amitriptyline upon spontaneous pupillary fluctuations in healthy human volunteers . Psychopharmacology149: 72–76 .
49.
Piercey M F (1998) Pharmacology of pramipexole, a dopamine D3-preferring agonist useful in treating Parkinson's disease . Clin Neuropharmacol21: 141–151 .
50.
Pigeau R , Naitoh P , Buguet A , McCann C , Baranski J , Taylor M , Thompson M , Mack I I (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 Res4: 212–228 .
51.
Rammohan K W , Rosenberg J H , Lynn D J , Blumenfeld A M , Pollak C P , Nagaraja H N (2002) Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study . J Neurol Neurosurg Psychiatry72: 179–183 .
52.
Randall D C , Fleck N L , Shneerson J M , File S E (2004) The cognitive enhancing properties of modafinil are limited in non-sleep-deprived middle-aged volunteers . Pharmacol Biochem Behav77: 547–555 .
53.
Randall D C , Shneerson J M , Plaha K K , File S E (2003) Modafinil affects mood, but not cognitive function, in healthy young volunteers . Hum Psychopharmacol18: 163–173 .
54.
Reichlin S (1998) Neuroendocrinology. In Wilson J D , Foster D W , Kronenberg H M , Larsen P R (eds), Williams Textbook of Endocrinology. WB Saunders Company, Philadelphia , pp. 165–248.
55.
Reichmann H , Brecht M H , Köster J , Kraus P H , Lemke M R (2003) Pramipexole in routine clinical practice: a prospective observational trial in Parkinson's disease . CNS Drugs17: 965–973 .
56.
Robertson P , Hellriegel E T (2003) Clinical pharmacokinetic profile of modafinil . Clin Pharmacokinet42: 123–137 .
57.
Rosenthal M H , Bryant S L (2004) Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia . Clin Neuropharmacol27: 38–43 .
58.
Rush C R , Kelly T H , Hays L R , Baker R W , Wooten A F (2002) Acute behavioural and physiological effects of modafinil in drug abusers . Behav Pharmacol13: 105–115 .
59.
Rye D B , Jankovic J (2002) Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD . Neurology58: 341–346 .
60.
Saper C B , Scammell T E (2004) Modafinil: a drug in search of a mechanism . Sleep27: 11–12 .
61.
Schilling J C , Adamus W S , Palluk R (1992) Neuroendocrine and side effect profile of pramipexole, a new dopamine receptor agonist, in humans . Clin Pharmacol Ther51: 541–548 .
62.
Smith J M , Misiak H (1976) Critical flicker frequency (CFF) and psychotropic drugs in normal human subjects – a review . Psychopharmacology47: 175–182 .
63.
Stivalet P , Esquivie D , Barraud P A , Leifflen D , Raphel C (1998) Effects of modafinil on attentional processes during 60 hours of sleep deprivation . Hum Psychopharmacol13: 501–507 .
64.
Svet-Moldovsky I , Svet-Moldovsky G , Zinzar S , Holland J , Vergara C , Arlin Z , Koziner B , Clarkson B (1981) The extracerebral dopamine antagonist domperidone block the suppressive effect of bromocriptine on prolactin and TSH secretion in man . Biomedicine35: 142–144 .
65.
Swanson L W (1982) The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat . Brain Res Bull9: 321–353 .
66.
Swanson L W , Sawchenko P E , Bérod A , Hartman B K , Helle K B , Vanorden D E (1981) An immunohistochemical study of the organisation of catecholaminergic cells and terminal fields in the paraventricular and supra optic nuclei of the hypothalamus . J Comp Neurol196: 271–285 .
67.
Szabadi E , Bradshaw C M (1996) Autonomic pharmacology of 2-adreno-ceptors . Journal of Psychopharmacology10(Suppl. 3): 6–18 .
68.
Szabadi E , Tavernor S (1999) Hypo and hypersalivation induced by psychoactive drugs . CNS Drugs11: 449–466 .
69.
Szabadi E , Langley R W , Bradshaw C M (2002) Comparison of single doses of noradrenergic drugs on pupillary fatigue waves in a patient with excessive daytime sleepiness . J Sleep Res11(Suppl. 1): 220-220 .
70.
Tan E K (2003) Piribedil-induced sleep attacks in Parkinson's disease . Fundam Clin Pharmacol17: 117–119 .
71.
Taneja I , Diedrich A , Black B K , Byrne D W , Paranjape S Y , Robertson D (2005) Modafinil elicits sympathomedullary activation . Hypertension45: 612–618 .
72.
Turner D C , Robbins T W , Clark L , Aron A R , Dowson J , Sahakian B J (2003) Cognitive enhancing effects of modafinil in healthy volunteers . Psychopharmacol165: 260–269 .
73.
Ulivelli M , Rossi S , Lombardi C , Bartalini S , Rocchi R , Giannini F , Passero S , Battistini N , Lugaresi E (2002) Polysomnographic characterization of pergolide-induced sleep attacks in idiopathic PD . Neurology58: 462–465 .
74.
US Modafinil in Narcolepsy Multicentre Study Group (1998) Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy . Ann Neurol43: 88–97 .
75.
US Modafinil in Narcolepsy Multicentre Study Group (2000) Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy . Neurology54: 1166–1175 .
76.
Vance M L , Kaiser D L , Frohman L A , Rivier J , Vale W W , Thorner M O (1987) Role of dopamine in the regulation of growth hormone secretion: dopamine and bromocriptine augment growth hormone (GH)releasing hormone – stimulated GH secretion in normal man . J Clin Endocrinol Metab64: 1136–1141 .
77.
Walsh J K , Randazzo A C , Stone K L , Schweitzer P K (2004) Modafinil improves alertness, vigilance, and executive function during simulated night shifts . Sleep27: 434–439 .
78.
Webster L , Andrews M , Stoddard G (2003) Modafinil treatment of opioidinduced sedation . Pain Med4: 135–140 .
79.
Wesensten N J , Belenky G , Kautz M A , Thorne D R , Reichardt R M , Balkin T J (2002) Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine . Psychopharmacol159: 238–247 .
80.
Wilhelm B , Giedke H , Lüdtke H , Bittner E , Hofmann A , Wilhelm H (2001) Daytime variations in central nervous system activation measured by a pupillographic sleepiness test . J Sleep Res10: 1–7 .
81.
Wisor J P , Nishino S , Sora I , Uhl G H , Mignot E , Edgar D M (2001) Dopaminergic role in stimulant-induced wakefulness . Journal of Neuroscience21: 1787–1794 .
82.
Wright C E , Lasher Sisson T , Ichhpurani A K , Peters G R (1997) Steady state pharmacokinetic properties of pramipexole in healthy volunteers . J Clin Pharmacol37: 520–525 .
83.
Yoss R E , Moyer N J , Hollenhurst R W (1970) Pupil size and spontaneous pupillary waves associated with alertness, drowsiness, and sleep . Neurology20: 545–554 .
