Wakefulness Promoting Meds
Wakefulness Promoting Meds
Wakefulness Promoting Meds
Abstract: Numerous studies dissecting the basic mechanisms that control sleep regulation have led to considerable improvement in our knowledge of sleep disorders. It is now well accepted that transitions between
sleep and wakefulness are regulated by complex neurobiologic mechanisms, which, ultimately, can be delineated as oscillations between two
opponent processes, one promoting sleep and the other promoting wakefulness. The role of several neurotransmitter or neuromodulator systems,
including noradrenergic, serotonergic, cholinergic, adenosinergic, and histaminergic systems and, more recently, the hypocretin/orexin and
dopamine systems, has been clearly established. Amphetamine-like stimulants are known to increase wakefulness by blocking dopamine reuptake, by stimulating dopamine release, or by both mechanisms. Modafinil
may increase wakefulness through activation of noradrenergic and
INTRODUCTION
Disclosure Statement
Drs. Boutrel and Koob have indicated no financial conflicts of interest.
Submitted for publication October 2003
Accepted for publication May 2004
Address correspondence to: Benjamin Boutrel, PhD, Centre de Neurosciences
Psychiatriques, 1er etage, Site de Cery, CH-1008 Prilly-Lausanne, Switzerland;
Tel: 41 21 643 6953; Fax: 41 21 643 6950; E-mail: [email protected]
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AMPHETAMINE-LIKE STIMULANTS
Introduction
Psychomotor stimulants are drugs that produce behavioral activation, usually accompanied by increases in arousal, motor activity, and alertness. One of the most commonly known psychostimulants, cocaine, is derived from the coca plant (Erythroxylon
coca) and has a long history as a stimulant. It has been used for
centuries in tonics and other preparations to allay fatigue.70,71
One class of stimulants, amphetamines, was synthesized originally as possible alternative drugs for the treatment of asthma and
was the principal component of the original benzedrine asthma
inhaler. They were used (and are still used) by the United States
military as antifatigue medications, and they currently are legally available for medical use as adjuncts for short-term weight
control, in attention-deficit/hyperactivity disorder, and in narcolepsy. Oral and intravenous doses of amphetamines increase
systolic and diastolic blood pressure and stimulate heart rate,
although high doses may induce a reflex slowing of the heart rate.
1183
Effects on Sleep
Amphetamine-like stimulants are known and consumed especially for their activity-sustaining effects (increased alertness,
strength, and endurance). Their wake-promoting properties are
obvious, but objective studies have clearly established their
effects on sleep. In rats, cocaine (6 mg/kg, orally and intraperitoneally administered) has been shown to induce a significant
increase in sleep latency and a reduction in total sleep time,
including a decrease in both slow-wave sleep and REM sleep.76
In humans, cocaine, amphetamines, and methylphenidate also
produce decreases in sleepiness, an increased latency to sleep,
and a drastic decrease in REM sleep associated with an increased
latency to the onset of this particular vigilance state.77-80
Molecular and Cellular Action of Amphetamine-like Stimulants in
the Brain
Amphetamine, methylphenidate, and cocaine are known to act
neuropharmacologically by enhancing the amount of
monoamines available within the synaptic cleft of monoamine
synapses in the central nervous system. They block the reuptake
and also enhance the release of norepinephrine, dopamine, and
serotonin.81-85 There is considerable evidence suggesting that the
primary neuropharmacologic action responsible for their psychostimulant effects is on the dopamine system in the central nervous system.86,87
The brain dopamine system can be divided into two major
pathways that originate in the midbrain and project to the forebrain and appear to be responsible for different aspects of psySLEEP, Vol. 27, No. 6, 2004
1184
produces a stress-like activation of the hypothalamic-pituitaryadrenocortical axis,118 leading to increased plasma corticosterone
in rats and plasma cortisol in humans, both known to promote
wakefulness.119,120
serotonin, or the hypothalamus-pituitary-adrenal axis) could participate in these wake-promoting effects is still a matter of
debate, but clearly amphetamine-like compounds require the
DAT for their wake-promoting effects.
MODAFINIL
Introduction
Management strategies for daytime sleepiness traditionally
have included lifestyle changes and the use of psychostimulants
(amphetamine, methylphenidate, pemoline) which have been
shown to efficiently enhance arousal.2 Despite this efficacy, some
patients or physicians may not be satisfied with psychostimulant
therapies, usually because of tolerance or, more often, adverse
events. For the last decade, modafinil has become a first-line
wake-promoting medication and a useful therapeutic alternative
to psychostimulant medications for the treatment of excessive
daytime sleepiness.126-129 Modafinil-mediated wake promotion
initially was reported to be the result of central 1-adrenoceptor
stimulation,130 but recent studies have linked this stimulant effect
to the selective activation of hypothalamocortical pathways (see
below) involved in the physiologic regulation of sleep and wakefulness.131 Modafinil is not a direct or indirect dopamine-receptor
agonist132-134 and has a low potential for abuse.135-138
Effects on Sleep
It has been shown that modafinil prolongs wakefulness in several species, apparently without associated behavioral excitation,
and its waking effect is not followed by any obvious sleep
rebound in the cat.130,133,139,140 In humans, modafinil is efficient
and well tolerated,141 with no evidence of tolerance developing
during 40 weeks of treatment.142 Nevertheless, a study based on
maintaining alertness and performance during sleep deprivation
has shown equivalent performance- and alertness-enhancing
effects after a single dose of either modafinil or caffeine, leading
to the conclusion that modafinil does not appear to offer advantages over caffeine (which is more readily available and less
expensive) for improving performance and alertness during sleep
loss in otherwise normal, healthy adults.143
Molecular and Cellular Action of Modafinil in the Brain
The wake-promoting mechanism of action of modafinil
remains uncertain, despite numerous reports of its neuropharmacologic action in the brain. Early studies highlighted the absence
of an interaction between modafinil and the dopamine system.132,134,144 It also was established that the dopamine D1/D2
antagonist haloperidol did not block the arousal effect of
modafinil, whereas it consistently decreased the amphetamineinduced increase in wakefulness.133 Finally, modafinil showed a
low affinity for dopamine reuptake sites.145 It has been suggested, therefore, that the arousal effects of modafinil could be related to noradrenergic neurotransmission, given that the arousal
produced by modafinil was blocked by 1 and adrenergic
receptor antagonists,133 and that modafinil affected the firing of
locus coeruleus noradrenergic neurons.132 Using c-Fos immunocytochemistry in cats, it has been shown that amphetamine and
methylphenidate do not share with modafinil the same pattern of
c-Fos activation in the brain.146 Indeed, whereas the use of
Summary
Amphetamine-like stimulants promote wakefulness by
enhancing the amount of dopamine available within the synaptic
cleft of dopamine synapses in the central nervous system. An
extended region of the medial basal forebrain, demarcated anteriorly by the anterior portion of the medial septal area and posteriorly by the posterior fraction of the preoptic area of the
hypothalamus has been hypothesized to be a possible candidate
to explain the action of amphetamines to initiate and maintain
alertness. Whether or not other systems (eg, norepinephrine,
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1185
Summary
Modafinil is an increasingly popular wake-promoting medication used for the treatment of narcolepsy due to its safety profile
and given that no obvious side effects have been reported. The
SLEEP, Vol. 27, No. 6, 2004
1186
neurons in the preoptic/anterior hypothalamus that are specifically active during sleep.48 Thus, by blocking the firing-rate cessation normally induced by adenosine, caffeine reinforces arousal
by two different and complementary mechanisms: (1) stimulation
of cholinergic neurons in the basal forebrain and (2) reinforcement of the inhibition exerted on sleep-promoting neurons.
Despite the ability of caffeine to increase vigilance, which is an
important reason why people consume caffeine, it has been suggested that the dopaminergic system also could contribute to the
widespread consumption of caffeine-containing beverages.167
However, while it has been clearly shown that caffeine induces
dopamine and glutamate release in the shell of the nucleus
accumbens,171 these actions are not thought to contribute to its
psychoactive effects.172-174 Furthermore, whereas DAT-knockout
mice are unresponsive to the normally robust wake-promoting
action of methamphetamine, these mice are hypersensitive to the
wake-promoting effects of caffeine.116
Actually, the adenosine A1 and A2a receptors seem to be primarily involved in the effects of caffeine on vigilance states,
whereas A2b and A3 receptors seem to play only a minor role
given that the inhibition of the actions of adenosine at this receptor level is incompatible with caffeine activity under physiologic
conditions.50 Adenosine A1 receptors are present in almost all
brain areas, with the highest levels in the hippocampus, cerebral
and cerebellar cortices, and certain thalamic nuclei.175,176 Only
moderate levels have been observed in the caudate putamen and
nucleus accumbens.177 Adenosine A2A receptors are found to be
concentrated in dopamine-rich regions of the brain and are colocalized with D2 receptors in rat striatum.178,179 Whereas caffeine
affects transmitter release and neuronal firing rates via actions on
adenosine A1 receptors, the effects of caffeine on dopaminergic
transmission are exerted mainly via actions on adenosine A2A
receptors.50 This indirect interaction of caffeine with the
dopamine system is through the opposite actions of adenosine A2a
receptors with dopamine D2 receptors.180,181 Indeed, it has been
shown that stimulation of adenosine A2a receptors opposes the
effect of dopamine at striatal output cells.182 Notably, dopamine
administered in the striatum has been shown to block release of
GABA in the globus pallidus183 and this effect is reduced by
endogenous adenosine. In line with this observation, it has been
observed that adenosine A2a receptor stimulation blocks the
inhibitory effect of a dopamine D2-receptor agonist on acetylcholine release from striatal slices.184 Finally, it has been suggested that a therapeutic potential exists for the use of A2a antagonists in the treatment of Parkinson disease.181This observation is
in line with the potential wake-promoting effect of A2a antagonists that could counterbalance the sleepiness usually observed in
Parkinson disease patients.
1187
an acute administration of nicotine (0.5 and 1.0 mg/kg, subcutaneously), an effect reversed by repeated administration of nicotine (0.1 mg/kg), suggesting that compensatory mechanisms are
triggered by chronic treatment.205
CONCLUSIONS
Excessive sleepiness is thought to result from the lack of maintenance of the arousal threshold, which, ultimately, alleviates the
inhibition exerted on the sleep-promoting system during wakefulness. Wake-promoting agents reinforce wakefulness by stimulating the release of neurotransmitters involved in the maintenance of the arousal threshold and, therefore, counterbalance the
inhibitory inputs from the sleep-promoting system to the wakepromoting one. Nicotine stimulates the cholinergic neurons in the
basal forebrain that lead to cortical activation. Caffeine participates to the cortical activation by blocking adenosine receptors
located on cholinergic neurons in the basal forebrain. Caffeine
also blocks adenosine receptors located on GABAergic neurons,
thus reinforcing the inhibition exerted on neurons in the preoptic/anterior hypothalamus that are involved in sleep induction and
may indirectly increase dopamine neurotransmission. Modafinil
may promote waking via activation of the tuberomammillary
nucleus and hypocretin neurons, which leads to an activation of
the ascending arousal system. The fact that either amphetaminelike stimulants or modafinil have failed to exert any waking
effect on DAT knockout mice suggests that the dopamine system
Summary
Nicotine enhances attention and vigilance likely by directly
stimulating cholinergic neurotransmission in the basal forebrain
responsible for cortical arousal. Interestingly, this observation
provides a biochemical explanation for the wake-promoting association for coffee and cigarettes. Nicotine stimulates cholinergic
neurotransmission and concomitantly enhances arousal, and caffeine limits the effects of sleepiness induced by increasing levels
of adenosine. Again, it can be hypothesized that the dopamine
system could play an indirect role in the wake-promoting properties of nicotine by mediating the enhanced motivational components of arousal.
SLEEP, Vol. 27, No. 6, 2004
1188
may play a role in the wake-promoting properties of these compounds. Understanding how wake-promoting drugs interact with
different components of the dopamine system to induce arousal
remains a challenge for future research to establish new stimulant
treatments.
18. Chen CT, Hwang LL, Chang JK, Dun NJ. Pressor effects of orexins injected intracisternally and to rostral ventrolateral medulla of
anesthetized rats. Am J Physiol Regul Integr Comp Physiol
2000;278:R692-7.
19. Date Y, Mondal MS, Matsukura S, et al. Distribution of
orexin/hypocretin in the rat median eminence and pituitary. Brain
Res Mol Brain Res 2000;76:1-6.
20. Hagan JJ, Leslie RA, Patel S, et al. Orexin A activates locus
coeruleus cell firing and increases arousal in the rat. Proc Natl Acad
Sci U S A 1999;96:10911-6.
21. Ida T, Nakahara K, Murakami T, Hanada R, Nakazato M,
Murakami N. Possible involvement of orexin in the stress reaction
in rats. Biochem Biophys Res Commun 2000;270:318-23.
22. Malendowicz LK, Tortorella C, Nussdorfer GG. Orexins stimulate
corticosterone secretion of rat adrenocortical cells, through the activation of the adenylate cyclase-dependent signaling cascade. J
Steroid Biochem Mol Biol 1999;70:185-8.
23. Nowak KW, Mackowiak P, Switonska MM, Fabis M, Malendowicz
LK. Acute orexin effects on insulin secretion in the rat: in vivo and
in vitro studies. Life Sci 2000;66:449-54.
24. Samson WK, Gosnell B, Chang JK, Resch ZT, Murphy TC.
Cardiovascular regulatory actions of the hypocretins in brain. Brain
Res 1999;831:248-53.
25. Shirasaka T, Kunitake T, Takasaki M, Kannan H. Neuronal effects
of orexins: relevant to sympathetic and cardiovascular functions.
Regul Pept 2002;104:91-5.
26. Bourgin P, Huitron-Resendiz S, Spier AD et al. Hypocretin-1 modulates rapid eye movement sleep through activation of locus
coeruleus neurons. J Neurosci 2000;20:7760-5.
27. Horvath TL, Peyron C, Diano S et al. Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic
system. J Comp Neurol 1999;415:145-59.
28. Ivanov A, Aston-Jones G. Hypocretin/orexin depolarizes and
decreases potassium conductance in locus coeruleus neurons.
Neuroreport 2000;11:1755-8.
29. Burlet S, Tyler CJ, Leonard CS. Direct and indirect excitation of
laterodorsal tegmental neurons by Hypocretin/Orexin peptides:
implications for wakefulness and narcolepsy. J Neurosci
2002;22:2862-72.
30. Brown RE, Sergeeva OA, Eriksson KS, Haas HL. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci
2002;22:8850-9.
31. Brown RE, Sergeeva O, Eriksson KS, Haas HL. Orexin A excites
serotonergic neurons in the dorsal raphe nucleus of the rat.
Neuropharmacology 2001;40:457-9.
32. Eriksson KS, Sergeeva O, Brown RE, Haas HL. Orexin/hypocretin
excites the histaminergic neurons of the tuberomammillary nucleus. J Neurosci 2001;21:9273-9.
33. Nakamura T, Uramura K, Nambu T et al. Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system. Brain Res 2000;873:181-7.
34. Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE.
Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci
2003;23:7-11.
35. Jaszberenyi M, Bujdoso E, Pataki I, Telegdy G. Effects of orexins
on the hypothalamic-pituitary-adrenal system. J Neuroendocrinol
2000;12:1174-8.
36. Kuru M, Ueta Y, Serino R et al. Centrally administered
orexin/hypocretin activates HPA axis in rats. Neuroreport
2000;11:1977-80.
37. Stricker-Krongrad A, Beck B. Modulation of hypothalamic
hypocretin/orexin mRNA expression by glucocorticoids. Biochem
Biophys Res Commun 2002;296:129-33.
38. Lin L, Faraco J, Li R et al. The sleep disorder canine narcolepsy is
ACKNOWLEDGMENTS
This is publication number 16145-NP from The Scripps
Research Institute. Benjamin Boutrel was supported by a fellowship from La Fondation pour la Recherche Medicale, France.
George Koob was supported by National Institutes of Health
grant DA04398 from the National Institute on Drug Abuse. The
authors would like to acknowledge the invaluable editorial assistance of Mike Arends in the preparation of this manuscript.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
1189
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
1190
1973;29:130-5.
84. Raiteri M, Bertollini A, Angelini F, Levi G. d-Amphetamine as a
releaser or reuptake inhibitor of biogenic amines in synaptosomes.
Eur J Pharmacol 1975;34:189-95.
85. Taylor D, Ho BT. Comparison of inhibition of monoamine uptake
by cocaine, methylphenidate and amphetamine. Res Commun
Chem Pathol Pharmacol 1978;21:67-75.
86. Koob GF, Sanna PP, Bloom FE. Neuroscience of addiction. Neuron
1998;21:467-76.
87. Koob GF. Drugs of abuse: anatomy, pharmacology and function of
reward pathways. Trends Pharmacol Sci 1992;13:177-84.
88. Koob GF. Hedonic valence, dopamine and motivation. Mol
Psychiatry 1996; :186-9.
89. Leshner AI, Koob GF. Drugs of abuse and the brain. Proc Assoc Am
Physicians 1999;111:99-108.
90. Kelley AE, Berridge KC. The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci 2002;22:3306-11.
91. DeLong MR. Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990;13:281-5.
92. Kebabian JW, Calne DB. Multiple receptors for dopamine. Nature
1979; 77:93-6.
93. Monsma FJ, Jr., Mahan LC, McVittie LD, Gerfen CR, Sibley DR.
Molecular cloning and expression of a D1 dopamine receptor
linked to adenylyl cyclase activation. Proc Natl Acad Sci U S A
1990;87:6723-7.
94. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC.
Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 1990;347:146-51.
95. Van Tol HH, Bunzow JR, Guan HC, et al. Cloning of the gene for
a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 1991;350:610-4.
96. Sunahara RK, Guan HC, O'Dowd BF, et al. Cloning of the gene for
a human dopamine D5 receptor with higher affinity for dopamine
than D1. Nature 1991;350:614-9.
97. Xu M, Moratalla R, Gold LH, et al. Dopamine D1 receptor mutant
mice are deficient in striatal expression of dynorphin and in
dopamine-mediated behavioral responses. Cell 1994; 9:729-42.
98. Baik JH, Picetti R, Saiardi A et al. Parkinsonian-like locomotor
impairment in mice lacking dopamine D2 receptors. Nature
1995;377:424-8.
99. Maldonado R, Saiardi A, Valverde O, Samad TA, Roques BP,
Borrelli E. Absence of opiate rewarding effects in mice lacking
dopamine D2 receptors. Nature 1997;388:586-9.
100. Narita M, Mizuo K, Mizoguchi H, et al. Molecular evidence for the
functional role of dopamine D3 receptor in the morphine-induced
rewarding effect and hyperlocomotion. J Neurosci 2003;23:100612.
101.
Rubinstein M, Phillips TJ, Bunzow JR, et al. Mice
lacking dopamine D4 receptors are supersensitive to ethanol,
cocaine, and methamphetamine. Cell 1997;90:991-1001.
102. Holmes A, Hollon TR, Gleason TC, et al. Behavioral characterization of dopamine D5 receptor null mutant mice. Behav Neurosci
2001;115:1129-44.
103. Hollon TR, Bek MJ, Lachowicz JE, et al. Mice lacking D5
dopamine receptors have increased sympathetic tone and are hypertensive. J Neurosci 2002;22:10801-10.
104. Giros B, Jaber M, Jones SR, Wightman RM, Caron MG.
Hyperlocomotion and indifference to cocaine and amphetamine in
mice lacking the dopamine transporter. Nature 1996;379:606-12.
105. Rocha BA, Fumagalli F, Gainetdinov RR, et al. Cocaine selfadministration in dopamine-transporter knockout mice. Nat
Neurosci 1998;1:132-7.
106. Spielewoy C, Roubert C, Hamon M, Nosten-Bertrand M, Betancur
C, Giros B. Behavioural disturbances associated with hyperdopaminergia in dopamine-transporter knockout mice. Behav
Pharmacol 2000;11:279-90.
SLEEP, Vol. 27, No. 6, 2004
1191
107. Budygin EA, John CE, Mateo Y, Jones SR. Lack of cocaine effect
on dopamine clearance in the core and shell of the nucleus accumbens of dopamine transporter knock-out mice. J Neurosci
2002;22:RC222.
108. Amalric M, Koob GF. Functionally selective neurochemical afferents and efferents of the mesocorticolimbic and nigrostriatal
dopamine system. Prog Brain Res 1993;99:209-26.
109. Koob GF, Le HT, Creese I. The D1 dopamine receptor antagonist
SCH 23390 increases cocaine self-administration in the rat.
Neurosci Lett 1987;79:315-20.
110. Bjijou Y, Stinus L, Le Moal M, Cador M. Evidence for selective
involvement of dopamine D1 receptors of the ventral tegmental
area in the behavioral sensitization induced by intra-ventral
tegmental area injections of D-amphetamine. J Pharmacol Exp Ther
1996;277:1177-87.
111. Vezina P. D1 dopamine receptor activation is necessary for the
induction of sensitization by amphetamine in the ventral tegmental
area. J Neurosci 1996;16:2411-20.
112. Xu M, Guo Y, Vorhees CV, Zhang J. Behavioral responses to
cocaine and amphetamine administration in mice lacking the
dopamine D= receptor. Brain Res 2000;852:198-207.
113. Parkes JD, Dahlitz M. Amphetamine prescription. Sleep
1993;16:201-3.
114. Berridge CW, Stalnaker TA. Relationship between low-dose
amphetamine-induced arousal and extracellular norepinephrine and
dopamine levels within prefrontal cortex. Synapse 2002;46:140-9.
115. Jones BE, Harper ST, Halaris AE. Effects of locus coeruleus lesions
upon cerebral monoamine content, sleep-wakefulness states and the
response to amphetamine in the cat. Brain Res 1977;124:473-96.
116. Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM.
Dopaminergic role in stimulant-induced wakefulness. J Neurosci
2001;21:1787-94.
117. Berridge CW, O'Neil J, Wifler K. Amphetamine acts within the
medial basal forebrain to initiate and maintain alert waking.
Neuroscience 1999;93:885-96.
118. Sarnyai Z, Shaham Y, Heinrichs SC. The role of corticotropinreleasing factor in drug addiction. Pharmacol Rev 2001;53:209-43.
119. Bradbury MJ, Dement WC, Edgar DM. Effects of adrenalectomy
and subsequent corticosterone replacement on rat sleep state and
EEG power spectra. Am J Physiol 1998;275:R555-65.
120. Steiger A. Sleep and the hypothalamo-pituitary-adrenocortical system. Sleep Med Rev 2002;6:125-38.
121. Gawin FH, Ellinwood EH, Jr. Cocaine and other stimulants.
Actions, abuse, and treatment. N Engl J Med 1988;318:1173-82.
122. Kessler RC, Crum RM, Warner LA, Nelson CB, Schulenberg J,
Anthony JC. Lifetime co-occurrence of DSM-III-R alcohol abuse
and dependence with other psychiatric disorders in the National
Comorbidity Survey. Arch Gen Psychiatry 1997;54:313-321.
123. Warner LA, Kessler RC, Hughes M, Anthony JC, Nelson CB.
Prevalence and correlates of drug use and dependence in the United
States. Results from the National Comorbidity Survey. Arch Gen
Psychiatry 1995;52:219-29.
124. Weddington WW, Brown BS, Haertzen CA, et al. Changes in
mood, craving, and sleep during short-term abstinence reported by
male cocaine addicts. A controlled, residential study. Arch Gen
Psychiatry 1990;47:861-8.
125. Griffith J. A study of illicit amphetamine drug traffic in Oklahoma
City. Am J Psychiatry 1966;123:560-9.
126. Boivin DB, Montplaisir J, Petit D, Lambert C, Lubin S. Effects of
modafinil on symptomatology of human narcolepsy. Clin
Neuropharmacol 1993;16:46-53.
127. Billiard M, Besset A, Montplaisir J, et al. Modafinil: a double-blind
multicentric study. Sleep 1994;17:S107-12.
128. Besset A, Chetrit M, Carlander B, Billiard M. Use of modafinil in
the treatment of narcolepsy: a long term follow-up study.
Neurophysiol Clin 1996;26:60-6.
What Keeps Us AwakeBoutrel and Koob
1192
1193
212. Louis M, Clarke PB. Effect of ventral tegmental 6-hydroxydopamine lesions on the locomotor stimulant action of nicotine in
rats. Neuropharmacology 1998;37:1503-13.
213. Shim I, Javaid JI, Wirtshafter D et al. Nicotine-induced behavioral
sensitization is associated with extracellular dopamine release and
expression of c-Fos in the striatum and nucleus accumbens of the
rat. Behav Brain Res 2001;121:137-47.
214. Reavill C, Stolerman IP. Locomotor activity in rats after administration of nicotinic agonists intracerebrally. Br J Pharmacol
1990;99:273-8.
215. Marubio LM, Gardier AM, Durier S et al. Effects of nicotine in the
dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptors. Eur J Neurosci
2003;17:1329-37.
216. O'Neill MF, Dourish CT, Iversen SD. Evidence for an involvement
of D1 and D2 dopamine receptors in mediating nicotine-induced
hyperactivity in rats. Psychopharmacology (Berl) 1991;104:34350.
217. Mamelak M, Scharf MB, Woods M. Treatment of narcolepsy with
gamma-hydroxybutyrate. A review of clinical and sleep laboratory
findings. Sleep 1986;9:285-9.
218. Mamelak M, Escriu JM, Stokan O. The effects of gamma-hydroxybutyrate on sleep. Biol Psychiatry 1977;12:273-88.
219. Scharf MB, Lai AA, Branigan B, Stover R, Berkowitz DB.
Pharmacokinetics of gammahydroxybutyrate (GHB) in narcoleptic
patients. Sleep 1998;21:507-14.
220. Lammers GJ, Arends J, Declerck AC, Ferrari MD, Schouwink G,
Troost J. Gammahydroxybutyrate and narcolepsy: a double-blind
placebo-controlled study. Sleep 1993;16:216-20.
221. Lapierre O, Montplaisir J, Lamarre M, Bedard MA. The effect of
gamma-hydroxybutyrate on nocturnal and diurnal sleep of normal
subjects: further considerations on REM sleep-triggering mechanisms. Sleep 1990;13:24-30.
222. Scrima L, Hartman PG, Johnson FH, Jr., Thomas EE, Hiller FC.
The effects of gamma-hydroxybutyrate on the sleep of narcolepsy
patients: a double-blind study. Sleep 1990;13:479-90.
223. Bernasconi R, Mathivet P, Bischoff S, Marescaux C. Gammahydroxybutyric acid: an endogenous neuromodulator with abuse
potential? Trends Pharmacol Sci 1999; 0:135-41.
224. Wong CG, Gibson KM, Snead OC, III. From the street to the brain:
neurobiology of the recreational drug gamma-hydroxybutyric acid.
Trends Pharmacol Sci 2004; 5:29-34.
225. Gervasi N, Monnier Z, Vincent P et al. Pathway-specific action of
gamma-hydroxybutyric acid in sensory thalamus and its relevance
to absence seizures. J Neurosci 2003;23:11469-78.
226. Nishino S, Mignot E. Pharmacological aspects of human and
canine narcolepsy. Prog Neurobiol 1997;52:27-78.
227. Lin JS, Sakai K, Vanni-Mercier G et al. Involvement of histaminergic neurons in arousal mechanisms demonstrated with H3-receptor ligands in the cat. Brain Res 1990;523:325-30.
228. Monti JM, Jantos H, Ponzoni A, Monti D. Sleep and waking during
acute histamine H3 agonist BP 2.94 or H3 antagonist carboperamide
(MR
16155)
administration
in
rats.
Neuropsychopharmacology 1996;15:31-5.
229. Monti JM, Jantos H, Boussard M, Altier H, Orellana C, Olivera S.
Effects of selective activation or blockade of the histamine H3
receptor on sleep and wakefulness. Eur J Pharmacol 1991;205:2837.
230. Komater VA, Browman KE, Curzon P, Hancock AA, Decker MW,
Fox GB. H3 receptor blockade by thioperamide enhances cognition
in
rats
without
inducing
locomotor
sensitization.
Psychopharmacology (Berl) 2003;167:363-72.
231. Vanni-Mercier G, Gigout S, Debilly G, Lin JS. Waking selective
neurons in the posterior hypothalamus and their response to histamine H3-receptor ligands: an electrophysiological study in freely
moving cats. Behav Brain Res 2003;144:227-41.
SLEEP, Vol. 27, No. 6, 2004
1194
232. Mieda M, Willie JT, Hara J et al. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model
of narcolepsy in mice. Proc Natl Acad Sci USA 2004;101:4649-54.