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The Journal of Neuroscience, March 1, 2001, 21(5):1787-1794
Dopaminergic Role in Stimulant-Induced Wakefulness
Jonathan P.
Wisor1,
Seiji
Nishino1,
Ichiro
Sora2,
George H.
Uhl2,
Emmanuel
Mignot1, and
Dale M.
Edgar1
1 Sleep Disorders Research Center, Department of
Psychiatry and Behavioral Sciences, Stanford University School of
Medicine, Stanford, California 94305, and 2 Molecular
Neurobiology Branch, Intramural Research Program, National Institute on
Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224
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ABSTRACT |
The role of dopamine in sleep regulation and in mediating the
effects of wake-promoting therapeutics is controversial. In this study,
polygraphic recordings and caudate microdialysate dopamine measurements
in narcoleptic dogs revealed that the wake-promoting antinarcoleptic
compounds modafinil and amphetamine increase extracellular dopamine in
a hypocretin receptor 2-independent manner. In mice, deletion of the
dopamine transporter (DAT) gene reduced non-rapid eye movement sleep
time and increased wakefulness consolidation independently from
locomotor effects. DAT knock-out mice were also unresponsive to the
normally robust wake-promoting action of modafinil, methamphetamine,
and the selective DAT blocker GBR12909 but were hypersensitive to the
wake-promoting effects of caffeine. Thus, dopamine transporters play an
important role in sleep regulation and are necessary for the specific
wake-promoting action of amphetamines and modafinil.
Key words:
sleep-wake cycle; modafinil; amphetamine; caffeine; hypocretin; dopamine; narcolepsy
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INTRODUCTION |
The monoamines serotonin (5-HT) and
norepinephrine (NE) (Steriade and McCarley, 1990 ; Jones, 2000; Siegel,
2000) and histamine (HA) (Monti, 1993; Lin et al., 1996; Steininger et
al., 1999; Jones, 2000), neuropeptides including hypocretin (orexin)
(Chemelli et al., 1999; Hagan et al., 1999; Lin et al., 1999), and
other transmitters including acetylcholine (Steriade and McCarley,
1990; Jones, 2000; Siegel, 2000), GABA (Jones, 2000; Steriade, 2000), and adenosine (Porkka-Heiskanen et al., 1997; Portas et al., 1997) have
been prominently implicated in sleep-wake regulation. In contrast,
many authors have assigned only a marginal role for dopamine (DA) in
sleep-wake control (Jones et al., 1973; Miller et al., 1983; Steinfels
et al., 1983). Electrical activities of acetylcholine, NE, 5-HT
(Steriade and McCarley, 1990), and HA (Monti, 1993; Steininger et al.,
1999) neurons display robust changes across sleep-wake states that
contrast with the limited alterations in firing rates of DA neurons
across stages of sleep and wakefulness (Miller et al., 1983; Steinfels
et al., 1983). The latter forms the basis of contemporary belief that
alteration in acetylcholine, 5-HT, NE, or HA are more critically
involved in regulating the cortical electroencephalogram (EEG)
desynchronization characteristics of wakefulness (Steriade and
McCarley, 1990; Monti, 1993; Lin et al., 1996; Steininger et al., 1999;
Jones, 2000; Siegel, 2000), whereas dopaminergic activity is thought to
mediate motor-related aspects of behaviors (Steinfels et al.,
1983).
The lack of covariance between electrophysiological measures and sleep
stages does not, however, obviate a role for dopamine in arousal state
control. Indeed, the terminal release of dopamine varies in concert
with arousal states (Trulson, 1985). In addition, lesions of
dopaminergic cell groups in the ventral tegmentum that project to the
forebrain produce marked reduction in behavioral arousal (Jones et al.,
1973), and human Parkinson's disease patients, who exhibit consistent
dopaminergic lesions but inconsistent alterations in other monoamines,
experience severe sleep disorders (Aldrich, 2000).
Uncertainties have also persisted about the molecular bases of
efficacious wake-promoting compounds, such as amphetamines and
modafinil. Amphetamines block plasma membrane transporters for DA, NE,
and 5-HT and inhibit the vesicular monoamine transporter (VMAT2),
releasing monoamines from the synaptic vesicles into which VMAT2 pumps
them (Seiden et al., 1993). Noradrenergic mechanisms have been proposed
to explain the wake-promoting effects of amphetamine-like stimulants
(Parkes, 1990; Fawcett and Busch, 1998). However, dopamine-specific reuptake blockers can promote wakefulness in normal and
sleep-disordered narcoleptic animals better than NE
transporter-selective blockers (Nishino and Mignot, 1997; Nishino et
al., 1998). Furthermore, the wake-promoting effect of amphetamine is
maintained after severe reduction of brain norepinephrine produced by
lesions of the noradrenergic cells of the locus ceruleus in cats
(Jones et al., 1977).
The mode of action of modafinil, a new wake-promoting compound used in
the treatment of sleepiness associated with narcolepsy (US Modafinil in
Narcolepsy Multicenter Study Group, 1998), is even more uncertain.
Studies have suggested that modafinil increases wakefulness by
activating  -1 noradrenergic transmission (Duteil et al., 1990;
Jouvet et al., 1991) or hypothalamic cells that contain the peptide
hypocretin (Chemelli et al., 1999), or that it may work by modulating
GABAergic tone (Ferraro et al., 1996). To identify the molecular basis
for the wake-promoting effects of amphetamines and modafinil, we
studied the responses to these compounds in narcoleptic canines, a
genetic model for excessive sleepiness, and in dopamine transporter
(DAT) knock-out mice.
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MATERIALS AND METHODS |
Canine subjects. Four narcoleptic canines (mean ± SD age, 3.8 ± 2.1 years; 26.5 ± 0.6 kg) born at Stanford
University were used in both polygraphic recording and microdialysis
experiments. Animals were anesthetized and surgically prepared for EEG
and electromyogram (EMG) recordings as described previously (Reid et
al., 1996; Nishino et al., 1998). All dogs were given 3-6 weeks to
recover before experiments were initiated. Dogs were kept in an 12 hr
light/dark cycle (lights on 7:00 A.M.) and were fed daily at 9:00 A.M. Room temperature was maintained at 22.2 ± 1.1°C
and relative humidity at 40%. All experimental procedures complied with institutional and National Institutes of Health guidelines for
treatment of experimental animals and with the Policy on the Use
of Animals in Neuroscience Research of the Society for Neuroscience.
Polygraphic evaluation of the wake-promoting effects of modafinil
and d-amphetamine in narcoleptic canines. Intravenous
injections of modafinil (5 mg/kg), d-amphetamine (0.1 mg/kg), or vehicle (DMSO, 1 ml/30 kg) were made under lights-on
conditions between 10:00 A.M. and 2:00 P.M., with EEG and EMG recorded
for 1 hr after injection. Recordings for active drug and vehicle
baseline were performed sequentially, separated by a 48 hr washout
period, and the order of injection (active drug followed by vehicle
or vehicle followed by active drug) was randomized in each
animal. Two recording sessions (modafinil and d-amphetamine
with respective vehicle injections) were done for each animal with at
least a 1 week interval between sessions. Polygraphic recordings were
visually scored in 30 sec epochs as wake, drowsy, light sleep, deep
sleep, rapid-eye movement (REM) sleep, or cataplexy (Nishino et al.,
1998).
Microdialysis measurements of the effects of modafinil and
d-amphetamine on extracellular dopamine in narcoleptic
canines. One to 2 months subsequent to the above described
polygraphic recording sessions, microdialysis probes were implanted
bilaterally into the caudate nucleus (lateral, 7.0 mm;
anteroposterior, 26-28 mm; height 20 mm from stereotaxic zero) and
anchored in place under isoflurane anesthesia. On each of the next
3 d, animals were connected to a dialysis inlet and perfused with
artificial CSF (2.0 µl/min) for 30 min before and 60 min after
intravenous injection of active drug (modafinil, 5 mg/kg; or
d-amphetamine, 0.1 mg/kg) or vehicle (DMSO, 1 ml/30 kg). One
injection was performed on each experimental day at 10:00 A.M., and the
order of the injections was randomized in each animal. Perfusate
samples were collected in 10 min bins throughout the perfusion period.
DA levels in each 10 min perfusate were measured using reverse-phase
HPLC (detection limit, 20 fmol) (Reid et al., 1996).
Murine subjects. Mice were bred at the National Institute on
Drug Abuse, National Institutes of Health (Baltimore, MD) and shipped
to Stanford University at age 3-6 months (Sora et al., 1998). DAT
knock-out ( /; n = 14; age, 240 ± 8 (±SEM) d;
weight, 24 ± 1 gm), littermate heterozygous (+/;
n = 11; age, 267 ± 45 d; weight, 33 ± 1 gm), and wild-type (+/+; n = 14; age, 291 ± 25 d; weight, 32 ± 1 gm) mice were anesthetized with
isoflurane (3% in medical grade oxygen) and surgically prepared for
EEG and EMG recording (Van Gelder et al., 1991). After 2-3 weeks of
postsurgical recovery, mice were isolated in separate compartments of a
sound-attenuated stainless steel recording chamber with ad
libitum food and water in an 12 hr light/dark cycle. Room
temperature was maintained at 24 ± 1°C throughout
experimentation. All experimental procedures complied with
institutional and National Institutes of Health guidelines for
treatment of experimental animals and with the Policy on the Use
of Animals in Neuroscience Research of the Society for Neuroscience.
Baseline sleep study. Mice were acclimated to the recording
apparatus for 3 d before the initiation of data collection. A 24 hr baseline recording of EEG, EMG, wheel-running activity, and drinking
behavior was initiated 18-24 hr after a visual animal health check.
The recording chamber remained sealed throughout the entire recording period.
Murine pharmacological experiments. +/+ and / mice were
subjected to pharmacological or vehicle (0.25% methylcellulose in physiological saline) treatments beginning the day after the above described baseline recordings. Injections were delivered once per week,
with each injection followed by a 6-8 d washout period, during which
mice remained in the recording chamber. Each injection was preceded by
a baseline 24 hr recording period and followed by a 24 hr posttreatment
period, during which time recording chambers remained sealed and
experimenters did not enter the room in which the chambers are located.
All treatments were delivered intraperitoneally 5 hr into the daily
light period (±30 min). Because the order of treatments was not
consistent across animals and because some mice did not receive all
treatments, sample sizes differed among treatments [sample sizes (+/+,
/): vehicle (9, 8); methamphetamine, 2 mg/kg (14, 10); GBR12909, 20 mg/kg (14, 6); modafinil, 90 mg/kg (10, 9) and 300 mg/kg (14, 6); and
caffeine, 2.5 mg/kg (10, 8), 10 mg/kg (12, 7), and 20 mg/kg (8, 0)].
Consequently, the data are treated as independent measures in
statistical comparisons of treatments.
Mouse data collection and analysis. The acquisition and
processing of EEG, EMG, wheel, and drink data by the SCORE algorithm are described in detail previously (Van Gelder et al., 1991). Digitized
EEG (bandpass, 1-30 Hz; digitization rate, 100 Hz), integrated EMG
(bandpass, 10-100 Hz), and wheel and drink signal (binary variables)
were stored in 10 sec epochs. Epochs were classified as wake, REM sleep
(REM), or non-REM sleep (NREM) by a pattern-matching algorithm (SCORE;
Van Gelder et al., 1991). The scoring of sleep states by the SCORE
algorithm was validated by visual inspection of individual epoch scores
for every animal.
Long-term mouse wheel-running activity recordings. A subset
of mice of each genotype (DAT +/+, n = 7; DAT +/,
n = 4; DAT /, n = 6) were subjected
to long-term (>7 d), continuous monitoring of wheel-running activity
under a 12 hr light/dark cycle. The mean daily waveform of wheel
activity from each animal was calculated by averaging the number of
minutes of wheel-running activity occurring within each hour of the
12 hr light/dark cycle over a 7 d period. The group mean
(±SEM) of these individual values was then calculated within each
genotype to determine mean group waveform.
Statistics: canine experiments. Statistical significance of
the effect of modafinil and d-amphetamine on wake time in
narcoleptic dogs when compared with respective vehicle sessions was
determined using Student's t test. Statistical significance
of the effects of modafinil and d-amphetamine on DA efflux
was assessed using repeated-measures ANOVA with a grouping factor
(treatment) and with Bonferroni's-Dunn's post hoc
comparisons with the vehicle session.
Statistics: murine experiments. The effect of genotype on
long-term wheel-running data were assessed using repeated-measures ANOVA with genotype as a factor. Effects of genotype on NREM time, REM
time, wake time, mean sleep bout duration, and mean wake bout duration
values from the undisturbed baseline period were assessed by one-way
ANOVA with genotype as a factor. Sleep bouts are defined as episodes of
sleep (NREM + REM) initiated by at least 2 consecutive 10 sec epochs of
sleep and terminated by at least two 10 sec epochs of wake. Wake bouts
are defined as episodes of wake initiated by at least 2 consecutive 10 sec epochs of wake and terminated by at least two 10 sec epochs of sleep.
Statistical significance of the effects of GBR12909 (20 mg/kg) and
modafinil (90 mg/kg) on sleep states in mice was determined separately
within each genotype. Repeated-measures ANOVA with treatment (vehicle
vs drug) as a factor was performed on NREM time, REM time, and wake
time during the 48 hr recording period encompassing injection. The
cumulative wake-promoting effects of GBR12909 (20 mg/kg), modafinil (90 mg/kg), and vehicle were determined by subtracting the number of
minutes of wake during each hour of the preinjection baseline period
from the number of minutes of wake during the corresponding hour of the
postinjection period on an hourly basis and cumulating these subtracted
values serially over the entire 24 hr postinjection period.
Repeated-measures ANOVA with treatment (vehicle vs drug) as a factor
was performed on cumulated wake value separately within each genotype.
The net wake-promoting effects of all pharmacological treatments and of
vehicle injection over the 5 hr immediately after injection were
quantified in the form of cumulated wake: the difference in minutes of
wake between the 5 hr immediately after injection and the corresponding
5 hr of the baseline day. Two-way ANOVA, with genotype as one factor
and treatment (pharmacological compound vs vehicle) as the other, was
performed separately for each compound to determine whether there was a
significant effect of genotype or of treatment on cumulated wake.
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RESULTS |
Modafinil increases cerebral dopamine release and wakefulness in a
hypocretin-independent manner
To address the possibility that dopamine mediates the
wake-promoting effect of modafinil and amphetamine, in vivo
dialysis was performed in freely moving narcoleptic canines. Systemic
administration of modafinil (5 mg/kg, i.v.) and
d-amphetamine (0.1 mg/kg, i.v.) significantly increased time
spent awake. The most pronounced effect on wakefulness was observed
during the first hour after injection (p < 0.01 for both treatments, compared with the respective vehicle treatment),
and the wake-promoting effects of modafinil and amphetamine were
equipotent. Thus, respective doses of modafinil (5 mg/kg) and
amphetamine (0.1 mg/kg) were administered intravenously to narcoleptic
animals while DA release was continuously monitored in striatal
extracellular fluid (Fig. 1). A
quantitatively similar significant increase in extracellular DA
concentration was observed with equipotent doses of either amphetamine
or modafinil (p < 0.01; repeated-measures
ANOVA). These observations indicate that hypocretin receptor 2 is not
required for the wake-promoting effects of modafinil and amphetamine or
for their effects on dopaminergic transmission.
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Figure 1.
Effect of modafinil and
d-amphetamine on wakefulness and caudate DA efflux in
narcoleptic hypocretin receptor 2 mutant dogs. Systemic administration
of modafinil (5 mg/kg, i.v.) and d-amphetamine (0.1 mg/kg, i.v.) equipotently increased time spent awake. The most
pronounced effect on wakefulness was observed during the first hour
after injection [inset; *p < 0.01 for both treatments compared with the respective vehicle treatment
(white bars) by Student's t test;
n = 4 per group; mean ± SEM].
Microdialysis experiments demonstrated that administration of
amphetamine and modafinil significantly increased extracellular DA
levels (p < 0.05;
d-amphetamine or modafinil relative to vehicle
treatment; repeated-measures ANOVA with Bonferroni's-Dunn's
post hoc comparisons; n = 4 per
group; mean ± SEM). The baseline DA concentrations (at time 0)
for modafinil and d-amphetamine sessions were 17.2 ± 3.1 and 17.6 ± 3.5 nM (mean ± SEM),
respectively, and did not differ statistically among treatments.
VEH, 1 ml of 100% DMSO; d-AMP,
d-amphetamine.
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DAT knock-out mice exhibit normal circadian patterns of inactivity
and activity
DAT knock-out homozygote (/), heterozygote (+/), and
wild-type littermates (+/+) displayed robust rhythms of activity that were entrained to the 12 hr light/dark cycle, with quiescence during the light phase and wheel running during the dark phase (Fig.
2). A moderate increase in wheel-running
activity was observed in DAT knock-out mice only during the latter
portion of the dark period (Fig. 2).
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Figure 2.
Entrained circadian rhythms of wheel-running
activity in wild-type (DAT +/+) and homozygous DAT knock-out (DAT
/) mice. Representative raster plots (top 2 panels)
show nocturnal consolidation of wheel-running and a lack of
wheel-running activity during the light phase in both DAT +/+ and DAT
/ mice. Group mean ± SEM waveforms are shown for DAT +/+
(filled triangles; n = 7),
DAT / (filled circles; n = 6), and heterozygous DAT +/ (open squares;
n = 4) mice in the bottom panel.
Tick marks in the raster plots denote when wheel-running
activity was present in 5 min bins. Light-dark bar at
the top denotes lighting schedule. Twenty-four hour
activity patterns of DAT / mice differ significantly from those of
DAT +/+ mice (p < 0.02; two-way
repeated-measures ANOVA), *p < 0.05; DAT/
versus DAT +/+; Bonferroni's-Dunn's post hoc
comparisons.
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Sleep architecture is altered in DAT knock-out mice in undisturbed
baseline conditions
When studied in undisturbed baseline conditions, mice of each
genotype displayed sleep and wakefulness that were normal by several
electrophysiological criteria, including EEG spectral analyses. However, sleep architecture differed considerably
among mice of the three genotypes (Table
1). Mice lacking both copies of the DAT
gene displayed a threefold increase in wake bout duration compared with
wild-type littermates (p < 0.017; post
hoc comparisons). Heterozygous (+/) mice exhibited wake bout
durations that were intermediate of DAT knock-out and wild-type (Fig.
3). NREM sleep as a percentage of
recording time and mean sleep bout duration were reduced in DAT
knock-out mice relative to wild-type mice (Table 1).
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Figure 3.
Mean ± SEM wake bout duration during 24 hr
baseline recordings in wild-type (+/+; n = 14),
heterozygous (+/; n = 11), and homozygous DAT
knock-out (n = 14) mice. One-way ANOVA indicated
significant genotype effect [p < 0.014; df = (2,36)]. *p < 0.05 versus DAT +/+;
Student's t test.
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The wake-promoting effects of classical stimulants and the
previously undefined stimulant modafinil are abolished in DAT knock-out
mice
To verify that inhibition of DAT function is capable of producing
increased wakefulness in mice, we examined the effect of GBR12909, a
highly specific DAT inhibitor, during the fifth hour of the daily light
period, when the majority of time is spent sleeping. A dose of GBR12909
that resulted in a 67.77 ± 12 (±SEM) min increase in wake time
in wild-type mice over a 5 hr period (p < 0.001; treatment × time interaction) (Fig.
4; see Fig. 6) failed to increase wake in
the DAT knock-out mouse (p > 0.1) (Fig. 4; see
Fig. 6). This result confirms that the wake-promoting effect of
GBR12909 requires functioning dopamine transporters.
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Figure 4.
Effect of GBR12909 (20 mg/kg) on
sleep states in wild-type (+/+) and DAT knock-out (/) mice. Data
are the percentages of time (mean ± SEM in 2 hr bins) in NREM,
REM, and wake in the 24 hr pretreatment and 24 hr posttreatment
periods. Open circles, Vehicle (0.25% methylcellulose
vehicle); filled circles, GBR12909 (20 mg/kg).
Arrows indicate injection. Light-dark
bars at the bottom of the
panels indicate lighting schedule. Two-way
repeated-measures ANOVA indicated postinjection treatment × time interactions in DAT +/+ (p < 0.001 for
wake; p < 0.003 for NREM; p < 0.011 for REM) but not DAT / (p > 0.1;
all states) mice. Sample sizes (+/+, /): vehicle (9, 8); GBR12909
(14, 6).
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The effect of modafinil on sleep architecture in wild-type and DAT
knock-out animals is shown in Figure 5,
and its wake-promoting effect is quantified in Figure
6. These data clearly demonstrate a
striking wake-promoting effect of modafinil in wild-type mice that is
abolished in DAT knock-out mice. Both modafinil and GBR12909 significantly increase wake time by at least 60 min over a 5 hr period
in wild-type mice (p < 0.001; repeated-measures
ANOVA) (Fig. 6). A significant but minor (<10 min) decrease in REM
sleep was seen in the DAT knock-out after modafinil treatment (Fig. 5).
However, the absence of a significant change in wake time in DAT
knock-out mice over the 24 hr posttreatment period
(p > 0.1; repeated-measures ANOVA) (Fig. 6)
confirms that DAT is required for the wake-promoting effects of
modafinil and GBR12909.
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Figure 5.
Effect of modafinil (90 mg/kg) on
sleep states in wild-type (+/+) and DAT knock-out (/) mice. Data
are the percentages of time (mean ± SEM in 2 hr bins) in NREM,
REM, and wake in the 24 hr pretreatment and 24 hr posttreatment
periods. Open circles, Vehicle (0.25% methylcellulose
vehicle); filled circles, modafinil (90 mg/kg).
Arrows indicate injection. Light-dark
bars at the bottom of the panels indicate
lighting schedule. Two-way repeated-measures ANOVA indicated
postinjection treatment × time interactions for wake, NREM, and
REM sleep in both DAT +/+ (p < 0.001 for
wake, NREM, and REM) and DAT / (p = 0.007, 0.004, and 0.007, respectively) mice, but increased wake after
modafinil administration was only observed in DAT +/+ mice. Sample
sizes (+/+, /): vehicle (9, 8); modafinil (10, 9).
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Figure 6.
Cumulative effects of GBR12909 (20 mg/kg) and of
modafinil (90 mg/kg) on wake in wild-type (+/+) and DAT knock-out
(/) mice. The cumulative change in wake time (mean ± SEM) in
the posttreatment period relative to the corresponding period of the
baseline 24 hr pretreatment period is shown for vehicle (open
circles) and drug treatment (filled
circles). Note large increase in wakefulness in DAT +/+ but not
DAT / animals. Two-way repeated-measures ANOVA within each genotype
indicated significant treatment effect and treatment × time
interaction in DAT +/+ but not in DAT /. *p < 0.05 drug versus vehicle; Bonferroni's-Dunn's post
hoc comparisons. Sample sizes (+/+, /): vehicle (9, 8);
GBR12909, (14, 6); modafinil (10, 9).
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To further characterize the role of dopaminergic components in the
effects of stimulants, the wake-promoting effects of methamphetamine were also examined. When wild-type mice were treated with
methamphetamine at the time of their maximal sleep tendency, 5 hr after
lights on, wakefulness was enhanced. Thus, modest doses of
methamphetamine increase wake time by >60 min over a 5 hr period (Fig.
7). Increased wake was associated with
reductions in both NREM and REM sleep times in wild-type animals (data
not shown). In sharp contrast, methamphetamine did not increase
wakefulness in DAT knock-out mice (Fig. 7). The absence of effect could
not be explained by the overall sleep reductions noted in DAT knock-out
animals because the baseline wake time (~40-50%/hr) did not differ
significantly between genotypes in the latter portion of the day (see
baseline data in Fig. 4 for circadian waveform).
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Figure 7.
Response to wake-promoting therapeutics in
DAT knock-out (/; open bars) and wild-type
(filled bars) mice. Data are reported as the
cumulative change in time awake (mean ± SEM) 5 hr after treatment
relative to corresponding baseline 24 hr earlier. Two-way ANOVA
indicated significant genotype × treatment interaction in
comparisons of individual pharmacological treatments versus vehicle
(p < 0.05, all treatments).
VEH, 0.25% methylcellulose vehicle;
METH, methamphetamine; GBR, GBR12909.
1p < 0.001;
2p < 0.025 between groups;
3p < 0.002 relative to vehicle;
Student's t test. Sample sizes (+/+, /): vehicle
(9, 8); methamphetamine, 2 mg/kg (14, 10); GBR12909, 20 mg/kg (14, 6);
modafinil, 90 mg/kg (10, 9) and 300 mg/kg (14, 6); caffeine, 2.5 mg/kg
(10, 8), 10 mg/kg (12, 7), and 20 mg/kg (8, 0).
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DAT knock-out mice are hypersensitive to the wake-promoting effect
of caffeine
Caffeine, a widely used wakefulness-enhancing agent, retained full
ability to enhance wakefulness in the DAT knock-out. In fact, these
mice were hypersensitive to the wake-promoting effect of caffeine,
exhibiting a threefold to fivefold greater increase in wake time
relative to wild-type mice in response to 2.5 or 10 mg/kg doses (Fig.
7).
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DISCUSSION |
Dopamine has been thought to play a minor role in sleep-wake
regulation, yet compounds that block DAT or enhance dopamine release
potently promote wakefulness. Such compounds are commonly used to treat
the sleep disorder narcolepsy. Using a multidisciplinary approach, we
now show that amphetamine-like compounds and modafinil require DAT for
their wake-promoting effects.
Recent experiments have shown that hypocretin-containing neurons
express Fos-immunoreactivity after modafinil treatment (Chemelli et
al., 1999), leading the authors to speculate that modafinil may
increase wakefulness by activating hypocretin-containing cells. Our
results now indicate that intact hypocretin transmission is not
required for the wake-promoting effect of modafinil. Indeed, this compound increases wakefulness in both hypocretin receptor 2-deficient canines (Fig. 1) and in hypocretin-deficient human patients
(Peyron et al., 2000). The finding that modafinil and amphetamine
induce similar increases in dopamine release at equipotent wake-promoting doses rather suggests that increased dopaminergic transmission mediates the effects of both compounds. Together with the
previously observed binding of amphetamine-like compounds (Nishino et
al., 1998) and modafinil (Mignot et al., 1994) to DAT, these
observations in the narcoleptic dog support the hypothesis that
both modafinil and amphetamine promote wakefulness primarily by
increasing dopaminergic tone and not by stimulating hypocretin transmission.
DAT knock-out mice have proven to be a powerful tool to help dissect
the molecular mechanisms for the effects of nonselective compounds that
interact with multiple monoaminergic transmitter systems. For example,
studies of DAT knock-out mice have implicated cocaine and amphetamine
interactions with DAT in cocaine- and amphetamine-induced locomotor
stimulation (Giros et al., 1996; Gainetdinov et al., 1999) but not in
cocaine reward (Sora et al., 1998). In the current study, this approach
was used to demonstrate dramatic baseline sleep-wake abnormalities and
a total absence of wake promotion after treatment with GBR12909,
methamphetamine, and modafinil. These results are consistent with
dopamine mediation of wake-promoting therapeutics (with the notable
exception of caffeine).
The present results indicate that, in the lifelong absence of DAT,
methamphetamine actions at other sites are not sufficient to promote
wakefulness. These results must be interpreted in light of the primary
effect of DAT knock-out but also in light of the possibility that
adaptations in the knock-out could disable normal wake-promoting
actions of amphetamine-like compounds at other monoaminergic sites. In
fact, the adaptations identified in the DAT knock-out mouse appear to
leave serotonin and norepinephrine systems either intact or
supersensitive to blockade. Gainetdinov et al. (1999) have interpreted
locomotor responses in the DAT knock-out to indicate that serotonergic
transmission is intact in the DAT knock-out, so that amphetamine has a
serotonin-mediated calming effect in these mice. Recently, we have
identified enhanced reward responses to selective norepinephrine and
serotonin blockers in DAT knock-outs (F. S. Hall, I. Sora, X. F. Li, and G. R. Uhl, unpublished results). No neurochemical
assessment or change in gene expression identified to date suggests
that serotonin or norepinephrine transmission is disabled in these mice
(Fumagalli et al., 1998; Q. Liu, F. S. Hall, H. P. Lesch, D. Murphy, I. Sora, and G. R. Uhl, unpublished results). Furthermore,
even if some occult compromise in noradrenergic transmission were
present in DAT knock-outs, it would be unlikely to be the primary cause
for the effects observed here because the wake-promoting effect of amphetamine is maintained after even severe reductions in brain norepinephrine produced by large noradrenergic lesions (Jones et al.,
1977). Heightened responsiveness to amphetamine occurs in
norepinephrine transporter knock-out mice (Xu et al., 2000). Other
evidence supports a dopaminergic link to wake-promoting effects of
psychostimulants. The wake-promoting effects of amphetamine and its
derivatives correlate with the magnitude of increase in extracellular
dopamine produced by these compounds and not with increased
extracellular norepinephrine (Kanbayashi et al., 2000). The highly
specific DAT inhibitor GBR12909 (Heikkila and Manzino, 1984) promotes
wake in wild-type mice (Fig. 4). Together, these observations suggest
that blockade of DAT, independent from that of norepinephrine, provides
the basis for the wake-promoting effect of amphetamine and its derivatives.
Increased consolidation of wakefulness and reduced NREM sleep time in
DAT knock-out mice relative to wild-type littermates parallel those
reported previously for locomotion in DAT knock-outs (Giros et al.,
1996; Gainetdinov et al., 1999), tempting one to speculate that the
observed sleep-wake effects are secondary to increased locomotor
activity. However, the sleep abnormalities identified in the DAT
knock-out mice were observed under undisturbed baseline conditions,
regardless of whether they exhibited locomotor wheel-running activity
or not. In addition, hyperactivity has been reported in the DAT
knock-out only in novel environments and not in home cage environments
(Giros et al., 1996; Gainetdinov et al., 1999). Indeed, wheel-running
data from the DAT knock-out (Fig. 2) suggest that these mice are
hyperactive only in novel environments, in contrast to home cage conditions.
Similarly, there are reasons to believe that the wake-promoting effects
of dopaminergic stimulants are independent from their locomotor
effects. Modafinil and low-dose GBR12909 promote wakefulness without
disproportionately increasing locomotor activity in normal dogs
(Shelton et al., 1995) and rats (Edgar and Seidel, 1997). The
wake-promoting doses of amphetamine used in this study are one-fifth of
those typically used to elicit hyperactivity (Giros et al., 1996;
Gainetdinov et al., 1999) and stereotypies (Grisel et al., 1997). This
differential potency is consistent with clinical experience suggesting
increased wakefulness at doses lower than those that produce locomotor
activation and inconsistent with the notion that locomotor effects are
the primary reason for amphetamine-induced wakefulness. Because
locomotor activation and stereotypies are mediated primarily by
dopaminergic projections to the nucleus accumbens and dorsal striatum,
respectively (Creese, 1983; Koob, 2000), the present model suggests
that other projections more sensitive to the effects of DAT inhibition
[e.g., cortical and/or basal forebrain projections (Koob, 2000)] may
be involved in the promotion of wakefulness. Dopamine turnover is much
higher in the prefrontal cortex than in the striatum (Bannon et al.,
1981), indicating a greater regulatory role for DAT, and therefore the potential for greater sensitivity to DAT blockers, in the cortex. The
fact that activation of the ventral tegmental dopaminergic system has
been shown to increase EEG power in the high-frequency range (Montaron
et al., 1982), a frequency reflecting cortical activation independently
of locomotor activity (Maloney et al., 1997), may suggest the
involvement of direct dopaminergic projections to the cortex.
Nonetheless, we cannot exclude the possibility of some overlap in the
circuitry that regulates higher-order motor control and that which
modulates sleep.
Another mechanism that may contribute to increased wake in the DAT
knock-out is the regulation of growth hormone-releasing hormone (GHRH).
Dopamine receptors in the hypothalamus inhibit hypothalamic GHRH
release (West et al., 1997). Because GHRH promotes sleep (Ehlers et
al., 1986), an inverse relationship would be expected between
dopaminergic tone and sleep time. In DAT knock-out mice, GHRH is
chronically low, with concomitant small body size (Bosse et al., 1997).
Impairment of the somatotropic axis could thus reduce sleep in DAT
knock-out mice. This hypothesis is supported by the fact that mice with
a genetically engineered deficiency in GHRH, resulting in dwarfism,
exhibit significantly less NREM sleep than wild-type control mice
(Zhang et al., 1996).
The mechanism by which caffeine induces wake is not certain, but no
direct action on DAT has been reported for this compound. Thus, its
wake-promoting effect in the DAT knock-out serves as a positive
control, indicating that the response to a wake-promoting compound that
acts at a site other than DAT is intact in the DAT knock-out. Caffeine
has a number of pharmacological effects, yet antagonism of adenosine
receptors by caffeine is the only known central pharmacological effect
that occurs in the range of doses produced by voluntary caffeine intake
(for review, see Fredholm et al., 1999). Still, actions at other sites
cannot be ruled out. Hypersensitivity to caffeine in DAT knock-out mice
may reflect adenosine-dopamine interactions in sleep regulation,
similar to those implicated in brain locomotor control systems (Garrett
and Griffiths, 1997). Reduced dopaminergic signaling produced by
dopamine D2 receptor knock-out is associated with
a reduced locomotor response to caffeine and with reduced adenosine
A2A receptor-dependent cAMP signaling (Zahniser
et al., 2000). This observation suggests that adenosine-dopamine
interactions are important in determining the stimulant effect of caffeine.
Our finding that a DAT gene deletion alters baseline sleep and
responsiveness to the major therapeutic wake-promoting agents has
important clinical applications. Severe and often untreated sleep
disorders are common in patients with dopaminergic dysfunction caused
by Parkinson's disease and Huntington's chorea (Wiegand et al., 1991;
Aldrich, 2000). Dopamine metabolism and receptor abnormalities also
occur in disorders of excessive daytime sleepiness, such as narcolepsy
(Nishino and Mignot, 1997), and in normal aging. The current data,
combined with observations that specific DAT gene polymorphic markers
(Gill et al., 1997) and sleep disorders (Corkum et al., 1999) are
associated with attention deficit hyperactivity disorder, suggest that
human variants at the DAT gene locus could predispose to vulnerability
to sleep-wake disorders. Finally, our observations with DAT knock-outs
provide a new major target for development of more efficacious
wake-promoting drugs. The clinical safety profile, low abuse potential,
and clinical success of modafinil suggest that selective DAT inhibitors
can have useful clinical applications and low side effect profiles when
compared with classical amphetamine-like stimulants. Because
amphetamine-like compounds are now prescribed to millions of patients
with a wide variety of sleep and psychiatric disorders, the utility of
highly selective DAT inhibitors may deserve reconsideration.
| |
FOOTNOTES |
Received Aug. 21, 2000; revised Dec. 12, 2000; accepted Dec. 21, 2000.
This research was supported in part by National Institutes of Health
Grants HL61594 and HL64243 (D.M.E.), MH12244 (J.P.W.), MH01600 (S.N.),
and NS-23724 (E.M.), and Air Force Office of Scientific Research
Grant F49620-95-1-0388 (D.M.E.). We are grateful to Wesley Seidel for
advice on data analysis and to Laura Alexandre, Ronny Tjon, Humberto
Garcia, and Dr. Takashi Kanbayashi for technical assistance. We are
especially grateful to Dr. William C. Dement for inspiration and
continued support of the basic sleep research program at Stanford University.
Correspondence should be addressed to Dr. Jonathan P. Wisor, Sleep
Disorders Research Center, Stanford University School of Medicine, 701 Welch Road #2226, Palo Alto, CA 94304. E-mail: jwisor{at}stanford.edu.
| |
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TOP
ABSTRACT
INTRODUCTION
