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Dopaminergic transmission and the sleep-wakefulness continuum in man
Neuropharmacology Vol. 29, No. 4, pp. 41 l-417, 1990 Printed in Great Britain
0028-3908/90 $3.00 + 0.00 Pergamon Press plc
DOPAMINERGIC TRANSMISSION AND THE SLEEP-WAKEFULNESS CONTINUUM IN MAN A. N. NICHOLSON Royal
Air Force
Institute
of Aviation
and FETA A. PASCOE
Medicine,
Farnborough,
(Accepted 11 December
Hampshire
GUI4
6SZ, U.K.
1989)
Summary-Modulation of dopaminergic transmission on daytime alertness and performance and on nocturnal sleep were studied in man using 30, 60 and 90 mg pemoline, a dopamimetic drug, and 2, 4 and 6mg pimozide, a dopamine receptor antagonist. Pemoline lengthened daytime sleep latencies and improved attention, and increased wakefulness during nocturnal sleep. Rapid eye movement (REM) sleep was reduced with 90 mg pemoline, but this was due entirely to increased wakefulness. Pimozide had little effect on overnight sleep, but increased the tendency to fall asleep and impaired performance during the day. These studies suggest that the effects of certain drugs which modulate the activity of neurotransmitters, involved in the control of sleep and wakefulness, may be related to the inherent level of activity
of the central nervous system. Modulation of the dopaminergic system can have a profound influence on the manifestation of wakefulness and vigilance, but is unlikely to modify directly the elaboration of REM sleep in man. Key words-sleep,
alertness, dopamine, man.
Drugs which modify noradrenergic or serotonergic transmission in man lead to changes in sleep continuity and in rapid eye movement (REM) sleep. With inhibition of noradrenergic or serotonergic transmission there is sedation or wakefulness, respectively, and in each case REM sleep is reduced (Nicholson and Pascoe, 1986, 1988). Changes in sleep continuity, brought about by such drugs, are related specifically to their individual activity, whereas suppression of REM sleep appears to arise from a non-specific imbalance of pharmacological control (McCarley, 1982; Nicholson, Belyavin and Pascoe, 1989). The effect of modulation of dopaminergic transmission on the complex nocturnal pattern of REM and non-REM sleep in man is less well defined than modulation of the noradrenergic and serotonergic systems. It is uncertain whether the influence of the dopaminergic system is restricted entirely to sleep continuity and whether reduced REM sleep, with drugs which modify the activity of dopamine, is merely secondary to changes in wakefulness. It is in this context that the present studies were carried out with pemoline, a dopamimetic drug, and pimozide, a dopamine receptor antagonist. The effects of these drugs have been observed, throughout the sleep-wakefulness continuum, on sleep latencies and performance during the day, and on sleep overnight.
daytime sleep latencies were made. The subjects were 6 healthy adults (3 males, 3 females) aged between 18 and 24 (mean 21.7) years. They were not taking any other medication, and on the previous night they abstained from alcohol and retired at their usual bedtime. On the day of an experiment they ate a light breakfast and avoided beverages containing caffeine. Performance sessions, which lasted 20min commenced at 08.30, 10.30, 12.30, 14.30, 16.30 and 18.30 hr and sleep latencies were measured immediately after each session. Medication was ingested between the second and third sessions at 11.30 hr. Each subject took, on separate occasions, 30, 60 and 90 mg pemoline, 2, 4 and 6 mg pimozide and two placebos. All medication was identical in appearance and the experiment was double-blind. Treatments were arranged in a pseudo-random order, balanced for linear sequence and a week separated each assessment. A light lunch was provided at 13.30 hr. Performance. The tasks were presented in individual booths and were digit symbol substitution (Nicholson and Pascoe, 1986), word recall, sustained attention and short term memory. A modified version of the Williams Word Memory Task (Williams, Reid and Lemmer, 1966) was used to assess word recall, with a list of 16 disassociated words presented on a monitor at a rate of one word every 3 sec. The words were two syllable nouns with a frequency of greater than 15 per million in general usage. Immediately after the presentations, the subjects were given 1 min to write down all the words recalled from the list. Sustained attention was measured over a period of 10 min, using a random series of letters, displayed on
METHODS Performance
and daytime
sleep latencies
To examine the effects of the drugs on alertness during the day, assessments of both performance and 411
412
A. N. NICHOLSONand PETAA. PASCOE
a monitor at a rate of l/set. Two letters, the critical stimulus, were also displayed continuously at the top left hand corner of the screen and the subjects were required to press a response button whenever the letters of the critical stimulus were presented consecutively during the random series. Response data and reaction times were recorded. A test of short term memory was presented during the second session of each day. Subjects were given I min to examine a set of 10 photographs of miscellaneous, unrelated objects and during the fourth session, 4 hr later, subjects were given 45 set to recall and write down as many objects as possible. During each session, subjects also assessed their mood and well-being on a series of 12 visual analogue scales and on the Stanford sleepiness scale (SSS) (Hoddes, Zarcone, Smythe, Phillips and Dement, 1973). Sleep latencies. Two channels of electroencephalographic (EEG) activity (C4-Al, 01-A2) and bilateral electro-oculographic activity were recorded and subjects were instructed to lie in bed quietly and to try to fall asleep. The test was terminated after the onset of stage 1 (drowsy) sleep or after 20 min if the sleep onset criterion was not met. The latency to stage 1 sleep was determined. Nocturnal sleep
The subjects were 6 heahhy males aged between 21 and 25 (mean 22.0) years. They were familiar with the laboratory and recording techniques and were not taking any other medication. They were required to refrain from napping and undue exercise, and to abstain from alcohol and caffeine during the day preceding an experimental night. Each subject ingested at “lights out” (23.00-23.30 hr), on separate occasions, 30,60 and 90 mg pemoline, 2,4 and 6 mg pimozide and two placebos. All medication was identical in appearance and the experiment was double-blind. Treatments were arranged in a pseudorandom order, balanced for linear sequence, and a week separated each assessment. The subjects slept in individual light-proofed and sound-attenuated rooms which were temperature (18 + I’C) and humidity (55 & 1%) controlled. Two channels of EEG activity (C4-Al, Ol-A2), together with the bilateral electro-oculograms (EOG) and the submental electromyogram (EMG), were recorded on a Grass 8-10 EEG machine, sited in an adjoining room, with a paper speed of 10 mmjsec. The 80% amplitude frequency response was 0.1-35 Hz for the EEG, l-15 Hz for the EOG and 5-70 Hz for the EMG, with a selective 50 Hz notch filter in each channel. Each sleep record was scored inde~ndentIy into 30 set epochs by two analysts according to conventional criteria. Differences in the annotation of sleep stages were resolved but did not occur in more than 5% of the epochs. From the sleep stage data, various
measures were derived for statistical analysis. Half an hour after awakening (07.00-07.30 hr), the subjects completed assessments of sleep and well-being and any persistent effects of the drugs were assessed 9 and 1I hr after ingestion, using digit symbol substitution and a choice reaction time task. Statistical analysis
Daytime visual analogue scales of mood and wellbeing were assigned ranks for each subject separately and the principal components of the correlation matrix of the ranks for the 12 measures were calculated. Two components were derived and, after varimax rotation, these were identified as measures of sleepiness and feelings associated with mood. Sleep latencies were censored at 20 min and so an iterative extension to a standard analysis of variance procedure was used to investigate this measure. Performance data were screened for possible effects of sequence using analysis of covariance on dummy variables (John and Quenuoille, 1977) and if an order effect was found it was used to correct the data for that particular task. Each of the measures from the daytime and nocturnal studies was investigated using analysis of variance. The assumptions of analysis of variancehomogeneity of variance, normality and additivitywere studied by considering transformations of the raw measures using the maximum likelihood method of Box and Cox (1964). The residuals from an analysis of variance, applied to the data using the selected transformation, were then examined after the method of Anscombe (1961) and, if appropriate, this transfo~ation was applied. Many of the transformations were logarithmic and so random variation and treatment effects were proportional rather than additive. Means of the raw sleep data are presented in the tables, although this apparently teads to minor inconsistencies with the results of the analysis. Backtransformed means are presented for performance and sleep latency data. After analysis of variance, the effects of the drugs on sleep measures and on differences between the means of daytime measures, before ingestion (08.30 and 10.30 hr) and the means of those early (12.30 and 14.30hr), late (16.30 and 18.30hr) and over all sessions (12.30, 14.30, 16.30 and 18.30 hr) after ingestion, were investigated. A planned comparison, using the means or mean differences for 6 subjects, was made between the two placebos. Each of the remaining treatments was compared with the mean of the two placebos using the multiple comparison method of Dunnett (1964). The test of each of these hypotheses was made with a specified size a posteriori and so no account was taken of the composite F test for differences between treatments. Linear trends of daytime measures, over the four sessions after ingestion, were compared amongst placebo and doses of each drug.
Dopaminergic transmission Table
I. Effect of drugs
on changes
413
in sleep latencies and subjective assessments from before (08.3t&lO.30 hr) to after (12.3&14.30, 16.3kl8.30, 12.30-18.30 hr) ingestion (means for 6 subjects) Pemoline (mg)
Pimozide (mg) Time (hr)
Placebo
2
4
6
30
60
90
08.3&10.30 12.30-14.30 16.30-18.30
12.2 4.8 10.6
16.1 4.2 3.4
14.5 5.8 3.4
7.4 12.3’ 28.5’;
1.3 41.2** 46.5”
12.0 62.0” 137.1’;
12.30-18.30
1.7
3.8
10.0 3.8 5.0 ** ~ 4.4
4.6
20.4**
46.9**
99.6”
08.30-10.30 12.30-14.30 16.3&18.30 12.31Kl8.30 08.3tX10.30 12.3tKl4.30 16.30-18.30 12.3tXl8.30
-0.29 -0.13 0.48 0.18 2.6 2.9 3.3 3.1
-0.64 -0.01 0.51 0.25 2.4 2.8 3.3 3.0
-0.18 0.07 1.56 0.82 2.5 3.0 4.3 3.6
0.35 -0.26 -0.43** -0.35’1 2.6 2.4 3.0 2.1
Measure Sleep latency (min)
Subjective sleepiness (arbitrary Visual analogue scales
Stanford
---*t
units):
sleepiness scale
Significance
~
-0.34 -0.23 0.99 0.38 2.4 3.2 3.6 3.4
-0.02 -0.85’ -0.58* -0.72** 2.6 2.2 2.4 2.3’
levels: *P < 0.05; **P < 0.01.
RESULTS
Performance and daytime sleep latencies The results are given in Tables 1 and 2. After pimozide there was a more marked reduction in daytime sleep latencies than after placebo (pooled doses P < 0.05), related mainly to the later (16.30-18.30 hr) sessions (pooled doses P < 0.01). Analysis of linear trends over the four sessions after ingestion showed an increase in the tendency to fall a’sleep with 2 and 6mg pimozide, compared with placebo (P < 0.01). Changes in subjective assessments after the ingestion of pimozide were not signific,lntly different from changes with placebo, but with the Stanford sleepiness scale there was a linear trend, with an increase in sleepiness over the four sessions after ingestion of 6mg pimozide, compared with placebo and with 2 and 4 mg pimozide (P < 0.05). The number of substitutions on the digit symbol substitution test was decreased after pimozide (2 and 4mg P < 0.05; 6 mg P < O.Ol), mainly during tihe later (16.30-18.30 hr) sessions (pooled doses 1’ < 0.01). The decline in performance over the four sessions after ingestion was greater with 6mg pimozide than with placebo (P < 0.01) and compared with 2 and 4 mg pimozide (P < 0.05). Linear trend analysis showed that errors of commission and Fable 2. Effect of drugs on changes in performance
omission on the sustained attention task increased over the four sessions, after ingestion of 6 mg pimozide, compared with placebo (P < 0.05), though errors of commission were decreased from before to after ingestion of 4mg pimozide (P < 0.05). There was a greater increase in daytime sleep latencies after each dose of pemoline (P < 0.01) and the effect was present during both early (12.30-14.30 hr) (30 mg P < 0.05; 60 and 90 mg P < 0.01) and late (16.30-18.30 hr) (P < 0.01) sessibns. The trend over the four sessions after ingestion showed a more marked increase in sleep latencies with 90 mg pemoline than with 30 mg (P < 0.05) and 60 mg (P < 0.01). Subjects f& less sleepy after pemoline than after placebo (60 mg P < 0.05; 30 and 90 mg P < 0.01) and with 90 mg differences were observed during both early (12.30-14.30 hr) and late (16.30-18.30 hr) sessions (P ~0.05). There was a greater reduction in Stanford sleepiness scale scores after 90mg pemoline (P < 0.05). Ninety milligrammes of pemoline improved sustained attention, with a greater increase in the number of correct responses (P < 0.05), mainly during the late (16.30-18.30 hr) sessions (P < 0.05) and a decrease in errors of omission (P < 0.05). Word recall was also increased with pemoline, compared with placebo (pooled doses P < 0.05).
from before (08.30-10.30 hr) to after (12.3&14.30, (means for 6 subiects)
16.30-18.30,
Pimozide (mg) hileasure Digit symbol substitution (No. of substitutions)
Sustained attention (No. of correct responses)
Word recall (No. of words recalled)
Significance
0.33 -0.30 -0.13 -0.22* 2.8 2.6 3.0 2.8
levels: *P < 0.05; l*P < 0.01.
12.30-18.30 hr) ingestion Pemoline (mg)
Time (hr)
Placebo
2
4
6
30
60
90
08.3&10.30 12.30-14.30 16.30-18.30
207.9 213.7 210.7
214.4 209.9 202.9
211.9 209.4 199.3
213.2 210.8 187.8
211.6 221.3 221.8
212.4 215.8 216.4
213.9 226.3 231.8
12.3C-18.30 08.30-10.30 12.3&14.30 16.3Ckl8.30 12.30-18.30 08.30-10.30 12.30-14.30 16.3&18.30 12.3tXl8.30
212.2 75. I 73.6 68.1 70.8 9.3 8.2 8.2 8.2
206.4’ 13.1 71.7 66.3 69.0 9.3 8.2 6.9 7.6
20*4*.3* 79.8 75. I 70.4 72.8 8.1 1.3 8.3 7.8
199.3+* 73.4 71.3 68.5 69.9 10.0 8.9 8.1 8.5
221.5 13.2 72.9 70.5 71.7 8.8 9.0 8.7 8.9 ~-
216.1 16.7 77.3 76.3 76.8 9.1 8.7 8.5 8.6 I
229.1 72.1 77.8 81.4’ 79.6’ 8.8 8.8 9.4 9.1
A. N. NICHOLSON and FVTA A. PASCOE
414
Table 3. Effect of drugs on various
measures (means for 6 subiectsf
SI#D
Pimozide (mg) Measure Total sleep time (min) Steep eficiency index? Steep onset latency (min) REM/non-REM ratio Latency (min) to state 3 sleep Latency (min) to REM sleep Number of awakenings Number of stage shifts
Pemoline (mg)
-
Transformation
Placebo
2
4
6
30
log, (500 - x)
457.3 0.94 13.9 0.33 12.7 91.5 4.3 129.6
466.6 0.96 10.1 0.36 15.4 87.3 4.5 110.8
464.8 0.96 IO.7 0.32 11.9 97.1 4.7 119.7 **
464.4 0.96 14.3 0.36 13.6 72.4 3.0 lar.8
451.4 0.93 15.4 0.37 13.3 85.9 6.3 116.2
tog, x log, X log, X log, (x + 1)
60
90
4 13.2f 0.85* 13.2 0.28 16.4 93.4 6.0 93.3**
380.6** 0.79** t4.8 0.28 11.9 87.2 8.3** 104.F
Significance levels: *P < 0.05; l*f < 0.01. tSleep effciency index: total sleep time/time in bed. Table 4. Effect of drugs on duration
fmin)
of
sleep stages over the whole night (means for 6 subjects) Pimozide (mg)
Sleea stage
Transformation
Awake
log, (x + If
1 2 3 4 3+4 REM
Pemoline (mg)
Placebo
2
4
6
30
60
90
6.8 27.7 220.8 44.0 49.8 93.8 113.0
6.5 26.7 223.5 39.2 52.3 91.5 t 22.8
7.3 24.3 235.1 38.3 56.0 94.3 110.2
3.4 21.5 237.3 31.3* 50.7 82.0 120.6
IO.8 26.5 221.3 39.8 41.0 80.8* 121.6
37.8* 30.0 212.9 29.6** 48.8 78.4* 92.3
59.4** 37.0 190.7’ 26.2** 43.7 69.9*’ 84.3C
Significance levels: *P < 0.05; **P < 0.01, Nocturnal
after the onset of sleep (P < 0.01). Stage 3 sieep was reduced with 60 and 90mg pemoline (P < 0,Ol) and total slow wave sleep (stages 3 + 4) was decreased with each dose (30 and 60 mg P < 0.05; 90mg P c 0.01). The largest dose of pemoline also led to reduced stage 2 sleep (P < 0.05) and the duration of REM sleep was decreased (P < 0.05), mainly during the second 200 min interval after the onset of sleep (P < 0.01). Latencies to REM sleep and ratios of REM to non-REM sleep were not altered. Sleep patterns of a subject with placebo and with 30,60 and 90mg pemoline are shown in Figure 2. Subjective assessments of sleep and well-being, completed the next morning, were not altered with either pemoline or pimozide, and there were no residual effects of pemoline on performance. Performance was not modified 9 hr after the ingestion of pimozide, but digit symbol substitution was impaired 11hr after 4 mg (P < 0.01) and 6 mg (P < 0.05).
sleep
The results are given in Tables 3-6. The effects of pimozide on nocturnal sleep were limited to reduced stage 3 sleep with 6mg (P < 0.05), without any change in the duration of total slow wave sleep (stages 3 + 4). The number of stage shifts during the night was decreased over the dose range (P < 0.01). Sleep patterns of a subject with placebo and with 6 mg pimozide are shown in Figure 1. Pemoline reduced total sleep time and sleep efficiency and the duration of awake activity was increased (60 mg P < 0.05; 90 mg P < 0.01). The number of awakenings was increased with 90mg (P < 0.01) and there were fewer stage shifts with both 60 and 90 mg (P < 0.01). An analysis of sleep in 200 min intervals showed that increased awake activity and stage 1 (drowsy) sleep with 60 and 90mg pemoline occurred mainly between 200 and 400 min
Table 5. Effect of drugs on duration (min) of awake + stage I (drowsy) sleep and REM sleep during 200 min intervals from the onset of sleep (means for 6 subjects) Pimozide (mg) Stage Awake + stage REM
1
Pemoline (mg)
Interval
Placebo
2
4
6
30
O-200 200-400 O-200 20+-400
13.4 14.3 32.7 58.0
17.2 14.5 28.3 68.9
7.9 15.1 31.8 54.2
9.6 11.1 33.5 59.8
17.2 11.4 35.3 58.9
90
60 9.6 47.4+* 34.6 42.5
14.8 62.2” 36.3 33.4**
Significance level: **P < 0.01. Table 6. Effect of drugs on digit symbol substitution (DSS) and choice reaction time (CRT) (means for 6 subjects) Time (hrf after ingestion 9 II
Pimozide (mg) Test
Placebo
2
DSS CRT (msec) DSS CRT (msec)
156.9 397.3 168.0 399.3
163.8 391.2 158.7 405.3
Significance levels: *P < 0.05; **P < 0.01.
4 145.3 41 I A 141.3** 423.1
Pemoline (mg) 6 144.0 409.0 145.0* 427.5
-
30
60
90
163.7 395.8 173.8 410.3
164.7 387.3 175.5 396.8
169.7 402.2 181.3 402.0
Dopaminergic transmission
415
stage
Sleep
Awake
Sta!&~and Stage 2 slow wave 1 Sleep ,
1
I
0
2
t
3
4
5
6
Steepstage Awake
7
PIMOZIDE
?I
I
I
Sh
6mg
I
Stage 1 and REM Stage 2 Slow way*
sleep
1
I
0
2
t
4
3
7
8
5
8h
Time
Fig. 1. Nocturnal sleep of a subject after placebo and after 6 mg pimozide; REM sleep is represented by the black bars and stages 3 and 4 sleep are combined as slow wave sleep. The effects of pimozide on sleep were limited and the normal pattern of REM sleep during the night was maintained.
Sleep stage
PLACEBO
Awake Stage 1 and 17
m
lm
I lull
II-
I -
IW
Stage 2 Slow wave
jw-
SlMP
P
1
0
1
2
3
4
5
6
7
8h
PEMOLlNE 30mg
Steep stage Awake Stage 1 ancl REM Stage 2 Slow wave sleep 0
f
2
3
4
5
Sleepstage
6
7
, 8h
PEMOLINE SOmg
Awake Stage 1 and REM Stage 2 Slow wave
sleep
i I
7
0 Awake
1
2
3
4
5
Sleep stage
8
7
8h
PEMOLINE gomg
Stage t and REM Stage 2 Slow wave sleep
I
’ lU b
i
i
4
i
6
b
Time
i
bh
Fig. 2. Nocturnal sleep of a subject after placebo and after 30, 60 and 90 mg pemoline; REM sleep is represented by the black bars and stages 3 and 4 are combined as slow wave sleep. There was a dose-related increase in awake activity, which led to reduced REM sleep with 90 mg, but with each dose of pemoline, REM periods occurred at similar times to those with placebo.
A. N. NICHOLSON and
416 DISCUSSION
In the present studies, modulation of central dopamine activity by pemoline, a dopamimetic drug, and by pimozide, a dopamine receptor antagonist, led to changes in the level of arousal. Pemoline increased wakefulness during nocturnal sleep and lengthened daytime sleep latencies and improved attention, while, though pimozide had little effect on overnight sleep, as shown previously in healthy individuals (Sagales and Erill, 1973, it increased the tendency to fall asleep and impaired performance during the day. These observations suggest that the influence of the dopaminergic system may vary over the sleepwakefulness continuum. It is of interest that, though both pemoline and pimozide modified the propensity to fall asleep during the day, only pemoline modulated wakefulness during sleep. The potentially activating influence of the dopaminergic system would appear to be minimal during sleep, but not necessarily maximal during wakefulness. This is consistent with studies which have shown that dopamine receptor antagonists are more effective in reducing wakefulness in rats during periods of maximum spontaneous activity when the turnover of dopamine is reported to be increased, than during periods of rest (Lemmer and Berger, 1978; Fornal, Wojcik and Radulovacki, 1982; Nagayama, Takagi and Takahashi, 1987). Daytime alertness is increased with dopamimetic agents and inhibitors of the uptake of 5-hydroxytryptamine (S-HT), and decreased with dopamine receptor antagonists, H, antihistamines and inhibitors of the uptake of noradrenaline (Nicholson and Pascoe, 1986, 1988; Nicholson, 1985) but the drugs in these groups, in similar doses, do not all lead to changes in sleep continuity. Those which increase alertness during the day also increase nocturnal wakefulness but those which decrease alertness may have a limited or be without an effect on sleep (Nicholson and Pascoe, 1986, 1988; Nicholson, Pascoe and Stone, 1985). It would, therefore, appear that some transmitters may be more concerned with the regulation of vigilance and alertness than with the underlying control of sleep and wakefulness. It is well established that drowsiness and impaired performance during the day occur with a wide range of neuroleptics. However, such effects may arise from activity other than dopamine receptor antagonism, in particular from blockade of qadrenergic and histamine H, receptors (Peroutka, UPrichard, Greenberg and Snyder, 1977; Richelson, 1984; Black, Richelson and Richardson, 1985). However, in this study reduced alertness with pimozide was related to modulation of dopaminergic transmission. Pimozide has little affinity for other neurotransmitter sites (Peroutka et al., 1977; Peroutka and Snyder, 1980) and so it is considered that sedation can arise from dopamine receptor antagonism alone.
PETAA. PASCOE
A further aspect of drugs which modulate monoaminergic transmission is their effect on REM sleep. Monoaminergic and cholinergic influences are believed to exert a reciprocal control on the appearance of REM sleep (McCarley, 1982) and drugs which alter noradrenergic or serotonergic transmission on the one hand, or cholinergic transmission on the other, disturb the balance between these factors, leading to a reduction in REM sleep, independent of any change in the duration of sleep (Sagales, Erill and Domino, 1975; Sitaram, Moore and Gillin, 1978; Nicholson and Pascoe, 1986, 1988). Decreased REM sleep with pemoline was due entirely to increased wakefulness, without any change in the ratio of REM to non-REM sleep and this is consistent with the recent analysis on the modulation of REM sleep by drugs which modify monoaminergic transmission (Nicholson et al., 1989). The absence of changes in REM sleep with pimozide and the lack of a direct effect of pemoline on REM activity clearly suggest that the dopaminergic system is unlikely to be involved directly in the elaboration of REM sleep in man. Changes in REM sleep, independent of those which arise from changes in the duration of sleep, with drugs such as chlorpromazine and nomifensine, which also modify dopaminergic transmission are, therefore, believed to be due to modulation of the activity of other neurotransmitters, particularly noradrenaline (Gaillard and Kafi, 1979; Nicholson, Pascoe and Stone, 1986). The present studies provide some evidence that the effect of drugs, which modify sleep and wakefulness, may be related to the level of activity of the central nervous system. Certainly, the level of daytime alertness can be either increased or decreased by the modulation of several monoaminergic transmitter systems, whereas sleep appears to be less susceptible to such alterations. In this way, systems may be concerned with the broad control of sleep and wakefulness and/or with the subtle regulation of vigilance. The dopaminergic system has a profound influence on the manifestation of wakefulness and vigilance but it is unlikely, like noradrenaline, 5-HT, acetylcholine, or even y-aminobutyric acid (GABA) (Belyavin and Nicholson, 1987), to be directly involved in the complex evolution of the depth of sleep or of REM sleep in man. Acknowledgements-The
authors are indebted to Dr A. Belyavin and Mrs A. Berry for statistical advice and to Miss
C. Turner
for assistance
in carrying
out the experiments.
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Nicholson A. N., Pascoe P. A. and Stone B. M. (1985) Histaminergic systems and sleep: studies in man with H 1 and H2 antagonists. Neuropharmacology 24: 245-250. Nicholson A. N., Pascoe P. A. and Stone B. M. (1986) Modulation of catecholamine transmission and sleep in man. Neuropharmacology 25: 271-274. Peroutka S. J. and Snyder S. H. (1980) Relationship of neuroleptic drug effects at brain dopamine, serotonin, cc-adrenergic, and histamine receptors to clinical potency. Am. J. Psychiat. 137: 1518-1522. Peroutka S. J., U’Prichard D. C., Greenberg D. A. and Synder S. H. (1977) Neuroleptic drug interactions with norepinephrine alpha receptor binding sites in rat brain. Neuropharmacology
16: 549-556.
Richelson E. (1984) Neuroleptic affinities for human brain receptors and their use in predicting adverse effects. J. clin. Psychiat. 45: 331-336.
Sagales T. and Erill S. (1975) Effects of central dopaminergic blockade with pimozide upon the EEG sleep stages of sleep in man. Psychopharmacologia (Berlin) 41: 53-56. Sagales T., Erill S. and Domino E. F. (1975) Effects of repeated doses of scopolamine on the electroencephalographic stages of sleep in normal volunteers. C/in. Pharmat. Ther. 18: 727-732.
Sitaram N., Moore A. M. and Gillin J. C. (1978) Experimental acceleration and slowing of REM sleep ultradian rhythm by cholinergic agonist and antagonist. Nature 274: 490-492.
Williams H. L., Reid W. and Lemmer B. (1966) Some effects of sleep loss on memory. Percept. Mot. Skills 23: 1287-1293.
0028-3908/90 $3.00 + 0.00 Pergamon Press plc
DOPAMINERGIC TRANSMISSION AND THE SLEEP-WAKEFULNESS CONTINUUM IN MAN A. N. NICHOLSON Royal
Air Force
Institute
of Aviation
and FETA A. PASCOE
Medicine,
Farnborough,
(Accepted 11 December
Hampshire
GUI4
6SZ, U.K.
1989)
Summary-Modulation of dopaminergic transmission on daytime alertness and performance and on nocturnal sleep were studied in man using 30, 60 and 90 mg pemoline, a dopamimetic drug, and 2, 4 and 6mg pimozide, a dopamine receptor antagonist. Pemoline lengthened daytime sleep latencies and improved attention, and increased wakefulness during nocturnal sleep. Rapid eye movement (REM) sleep was reduced with 90 mg pemoline, but this was due entirely to increased wakefulness. Pimozide had little effect on overnight sleep, but increased the tendency to fall asleep and impaired performance during the day. These studies suggest that the effects of certain drugs which modulate the activity of neurotransmitters, involved in the control of sleep and wakefulness, may be related to the inherent level of activity
of the central nervous system. Modulation of the dopaminergic system can have a profound influence on the manifestation of wakefulness and vigilance, but is unlikely to modify directly the elaboration of REM sleep in man. Key words-sleep,
alertness, dopamine, man.
Drugs which modify noradrenergic or serotonergic transmission in man lead to changes in sleep continuity and in rapid eye movement (REM) sleep. With inhibition of noradrenergic or serotonergic transmission there is sedation or wakefulness, respectively, and in each case REM sleep is reduced (Nicholson and Pascoe, 1986, 1988). Changes in sleep continuity, brought about by such drugs, are related specifically to their individual activity, whereas suppression of REM sleep appears to arise from a non-specific imbalance of pharmacological control (McCarley, 1982; Nicholson, Belyavin and Pascoe, 1989). The effect of modulation of dopaminergic transmission on the complex nocturnal pattern of REM and non-REM sleep in man is less well defined than modulation of the noradrenergic and serotonergic systems. It is uncertain whether the influence of the dopaminergic system is restricted entirely to sleep continuity and whether reduced REM sleep, with drugs which modify the activity of dopamine, is merely secondary to changes in wakefulness. It is in this context that the present studies were carried out with pemoline, a dopamimetic drug, and pimozide, a dopamine receptor antagonist. The effects of these drugs have been observed, throughout the sleep-wakefulness continuum, on sleep latencies and performance during the day, and on sleep overnight.
daytime sleep latencies were made. The subjects were 6 healthy adults (3 males, 3 females) aged between 18 and 24 (mean 21.7) years. They were not taking any other medication, and on the previous night they abstained from alcohol and retired at their usual bedtime. On the day of an experiment they ate a light breakfast and avoided beverages containing caffeine. Performance sessions, which lasted 20min commenced at 08.30, 10.30, 12.30, 14.30, 16.30 and 18.30 hr and sleep latencies were measured immediately after each session. Medication was ingested between the second and third sessions at 11.30 hr. Each subject took, on separate occasions, 30, 60 and 90 mg pemoline, 2, 4 and 6 mg pimozide and two placebos. All medication was identical in appearance and the experiment was double-blind. Treatments were arranged in a pseudo-random order, balanced for linear sequence and a week separated each assessment. A light lunch was provided at 13.30 hr. Performance. The tasks were presented in individual booths and were digit symbol substitution (Nicholson and Pascoe, 1986), word recall, sustained attention and short term memory. A modified version of the Williams Word Memory Task (Williams, Reid and Lemmer, 1966) was used to assess word recall, with a list of 16 disassociated words presented on a monitor at a rate of one word every 3 sec. The words were two syllable nouns with a frequency of greater than 15 per million in general usage. Immediately after the presentations, the subjects were given 1 min to write down all the words recalled from the list. Sustained attention was measured over a period of 10 min, using a random series of letters, displayed on
METHODS Performance
and daytime
sleep latencies
To examine the effects of the drugs on alertness during the day, assessments of both performance and 411
412
A. N. NICHOLSONand PETAA. PASCOE
a monitor at a rate of l/set. Two letters, the critical stimulus, were also displayed continuously at the top left hand corner of the screen and the subjects were required to press a response button whenever the letters of the critical stimulus were presented consecutively during the random series. Response data and reaction times were recorded. A test of short term memory was presented during the second session of each day. Subjects were given I min to examine a set of 10 photographs of miscellaneous, unrelated objects and during the fourth session, 4 hr later, subjects were given 45 set to recall and write down as many objects as possible. During each session, subjects also assessed their mood and well-being on a series of 12 visual analogue scales and on the Stanford sleepiness scale (SSS) (Hoddes, Zarcone, Smythe, Phillips and Dement, 1973). Sleep latencies. Two channels of electroencephalographic (EEG) activity (C4-Al, 01-A2) and bilateral electro-oculographic activity were recorded and subjects were instructed to lie in bed quietly and to try to fall asleep. The test was terminated after the onset of stage 1 (drowsy) sleep or after 20 min if the sleep onset criterion was not met. The latency to stage 1 sleep was determined. Nocturnal sleep
The subjects were 6 heahhy males aged between 21 and 25 (mean 22.0) years. They were familiar with the laboratory and recording techniques and were not taking any other medication. They were required to refrain from napping and undue exercise, and to abstain from alcohol and caffeine during the day preceding an experimental night. Each subject ingested at “lights out” (23.00-23.30 hr), on separate occasions, 30,60 and 90 mg pemoline, 2,4 and 6 mg pimozide and two placebos. All medication was identical in appearance and the experiment was double-blind. Treatments were arranged in a pseudorandom order, balanced for linear sequence, and a week separated each assessment. The subjects slept in individual light-proofed and sound-attenuated rooms which were temperature (18 + I’C) and humidity (55 & 1%) controlled. Two channels of EEG activity (C4-Al, Ol-A2), together with the bilateral electro-oculograms (EOG) and the submental electromyogram (EMG), were recorded on a Grass 8-10 EEG machine, sited in an adjoining room, with a paper speed of 10 mmjsec. The 80% amplitude frequency response was 0.1-35 Hz for the EEG, l-15 Hz for the EOG and 5-70 Hz for the EMG, with a selective 50 Hz notch filter in each channel. Each sleep record was scored inde~ndentIy into 30 set epochs by two analysts according to conventional criteria. Differences in the annotation of sleep stages were resolved but did not occur in more than 5% of the epochs. From the sleep stage data, various
measures were derived for statistical analysis. Half an hour after awakening (07.00-07.30 hr), the subjects completed assessments of sleep and well-being and any persistent effects of the drugs were assessed 9 and 1I hr after ingestion, using digit symbol substitution and a choice reaction time task. Statistical analysis
Daytime visual analogue scales of mood and wellbeing were assigned ranks for each subject separately and the principal components of the correlation matrix of the ranks for the 12 measures were calculated. Two components were derived and, after varimax rotation, these were identified as measures of sleepiness and feelings associated with mood. Sleep latencies were censored at 20 min and so an iterative extension to a standard analysis of variance procedure was used to investigate this measure. Performance data were screened for possible effects of sequence using analysis of covariance on dummy variables (John and Quenuoille, 1977) and if an order effect was found it was used to correct the data for that particular task. Each of the measures from the daytime and nocturnal studies was investigated using analysis of variance. The assumptions of analysis of variancehomogeneity of variance, normality and additivitywere studied by considering transformations of the raw measures using the maximum likelihood method of Box and Cox (1964). The residuals from an analysis of variance, applied to the data using the selected transformation, were then examined after the method of Anscombe (1961) and, if appropriate, this transfo~ation was applied. Many of the transformations were logarithmic and so random variation and treatment effects were proportional rather than additive. Means of the raw sleep data are presented in the tables, although this apparently teads to minor inconsistencies with the results of the analysis. Backtransformed means are presented for performance and sleep latency data. After analysis of variance, the effects of the drugs on sleep measures and on differences between the means of daytime measures, before ingestion (08.30 and 10.30 hr) and the means of those early (12.30 and 14.30hr), late (16.30 and 18.30hr) and over all sessions (12.30, 14.30, 16.30 and 18.30 hr) after ingestion, were investigated. A planned comparison, using the means or mean differences for 6 subjects, was made between the two placebos. Each of the remaining treatments was compared with the mean of the two placebos using the multiple comparison method of Dunnett (1964). The test of each of these hypotheses was made with a specified size a posteriori and so no account was taken of the composite F test for differences between treatments. Linear trends of daytime measures, over the four sessions after ingestion, were compared amongst placebo and doses of each drug.
Dopaminergic transmission Table
I. Effect of drugs
on changes
413
in sleep latencies and subjective assessments from before (08.3t&lO.30 hr) to after (12.3&14.30, 16.3kl8.30, 12.30-18.30 hr) ingestion (means for 6 subjects) Pemoline (mg)
Pimozide (mg) Time (hr)
Placebo
2
4
6
30
60
90
08.3&10.30 12.30-14.30 16.30-18.30
12.2 4.8 10.6
16.1 4.2 3.4
14.5 5.8 3.4
7.4 12.3’ 28.5’;
1.3 41.2** 46.5”
12.0 62.0” 137.1’;
12.30-18.30
1.7
3.8
10.0 3.8 5.0 ** ~ 4.4
4.6
20.4**
46.9**
99.6”
08.30-10.30 12.30-14.30 16.3&18.30 12.31Kl8.30 08.3tX10.30 12.3tKl4.30 16.30-18.30 12.3tXl8.30
-0.29 -0.13 0.48 0.18 2.6 2.9 3.3 3.1
-0.64 -0.01 0.51 0.25 2.4 2.8 3.3 3.0
-0.18 0.07 1.56 0.82 2.5 3.0 4.3 3.6
0.35 -0.26 -0.43** -0.35’1 2.6 2.4 3.0 2.1
Measure Sleep latency (min)
Subjective sleepiness (arbitrary Visual analogue scales
Stanford
---*t
units):
sleepiness scale
Significance
~
-0.34 -0.23 0.99 0.38 2.4 3.2 3.6 3.4
-0.02 -0.85’ -0.58* -0.72** 2.6 2.2 2.4 2.3’
levels: *P < 0.05; **P < 0.01.
RESULTS
Performance and daytime sleep latencies The results are given in Tables 1 and 2. After pimozide there was a more marked reduction in daytime sleep latencies than after placebo (pooled doses P < 0.05), related mainly to the later (16.30-18.30 hr) sessions (pooled doses P < 0.01). Analysis of linear trends over the four sessions after ingestion showed an increase in the tendency to fall a’sleep with 2 and 6mg pimozide, compared with placebo (P < 0.01). Changes in subjective assessments after the ingestion of pimozide were not signific,lntly different from changes with placebo, but with the Stanford sleepiness scale there was a linear trend, with an increase in sleepiness over the four sessions after ingestion of 6mg pimozide, compared with placebo and with 2 and 4 mg pimozide (P < 0.05). The number of substitutions on the digit symbol substitution test was decreased after pimozide (2 and 4mg P < 0.05; 6 mg P < O.Ol), mainly during tihe later (16.30-18.30 hr) sessions (pooled doses 1’ < 0.01). The decline in performance over the four sessions after ingestion was greater with 6mg pimozide than with placebo (P < 0.01) and compared with 2 and 4 mg pimozide (P < 0.05). Linear trend analysis showed that errors of commission and Fable 2. Effect of drugs on changes in performance
omission on the sustained attention task increased over the four sessions, after ingestion of 6 mg pimozide, compared with placebo (P < 0.05), though errors of commission were decreased from before to after ingestion of 4mg pimozide (P < 0.05). There was a greater increase in daytime sleep latencies after each dose of pemoline (P < 0.01) and the effect was present during both early (12.30-14.30 hr) (30 mg P < 0.05; 60 and 90 mg P < 0.01) and late (16.30-18.30 hr) (P < 0.01) sessibns. The trend over the four sessions after ingestion showed a more marked increase in sleep latencies with 90 mg pemoline than with 30 mg (P < 0.05) and 60 mg (P < 0.01). Subjects f& less sleepy after pemoline than after placebo (60 mg P < 0.05; 30 and 90 mg P < 0.01) and with 90 mg differences were observed during both early (12.30-14.30 hr) and late (16.30-18.30 hr) sessions (P ~0.05). There was a greater reduction in Stanford sleepiness scale scores after 90mg pemoline (P < 0.05). Ninety milligrammes of pemoline improved sustained attention, with a greater increase in the number of correct responses (P < 0.05), mainly during the late (16.30-18.30 hr) sessions (P < 0.05) and a decrease in errors of omission (P < 0.05). Word recall was also increased with pemoline, compared with placebo (pooled doses P < 0.05).
from before (08.30-10.30 hr) to after (12.3&14.30, (means for 6 subiects)
16.30-18.30,
Pimozide (mg) hileasure Digit symbol substitution (No. of substitutions)
Sustained attention (No. of correct responses)
Word recall (No. of words recalled)
Significance
0.33 -0.30 -0.13 -0.22* 2.8 2.6 3.0 2.8
levels: *P < 0.05; l*P < 0.01.
12.30-18.30 hr) ingestion Pemoline (mg)
Time (hr)
Placebo
2
4
6
30
60
90
08.3&10.30 12.30-14.30 16.30-18.30
207.9 213.7 210.7
214.4 209.9 202.9
211.9 209.4 199.3
213.2 210.8 187.8
211.6 221.3 221.8
212.4 215.8 216.4
213.9 226.3 231.8
12.3C-18.30 08.30-10.30 12.3&14.30 16.3Ckl8.30 12.30-18.30 08.30-10.30 12.30-14.30 16.3&18.30 12.3tXl8.30
212.2 75. I 73.6 68.1 70.8 9.3 8.2 8.2 8.2
206.4’ 13.1 71.7 66.3 69.0 9.3 8.2 6.9 7.6
20*4*.3* 79.8 75. I 70.4 72.8 8.1 1.3 8.3 7.8
199.3+* 73.4 71.3 68.5 69.9 10.0 8.9 8.1 8.5
221.5 13.2 72.9 70.5 71.7 8.8 9.0 8.7 8.9 ~-
216.1 16.7 77.3 76.3 76.8 9.1 8.7 8.5 8.6 I
229.1 72.1 77.8 81.4’ 79.6’ 8.8 8.8 9.4 9.1
A. N. NICHOLSON and FVTA A. PASCOE
414
Table 3. Effect of drugs on various
measures (means for 6 subiectsf
SI#D
Pimozide (mg) Measure Total sleep time (min) Steep eficiency index? Steep onset latency (min) REM/non-REM ratio Latency (min) to state 3 sleep Latency (min) to REM sleep Number of awakenings Number of stage shifts
Pemoline (mg)
-
Transformation
Placebo
2
4
6
30
log, (500 - x)
457.3 0.94 13.9 0.33 12.7 91.5 4.3 129.6
466.6 0.96 10.1 0.36 15.4 87.3 4.5 110.8
464.8 0.96 IO.7 0.32 11.9 97.1 4.7 119.7 **
464.4 0.96 14.3 0.36 13.6 72.4 3.0 lar.8
451.4 0.93 15.4 0.37 13.3 85.9 6.3 116.2
tog, x log, X log, X log, (x + 1)
60
90
4 13.2f 0.85* 13.2 0.28 16.4 93.4 6.0 93.3**
380.6** 0.79** t4.8 0.28 11.9 87.2 8.3** 104.F
Significance levels: *P < 0.05; l*f < 0.01. tSleep effciency index: total sleep time/time in bed. Table 4. Effect of drugs on duration
fmin)
of
sleep stages over the whole night (means for 6 subjects) Pimozide (mg)
Sleea stage
Transformation
Awake
log, (x + If
1 2 3 4 3+4 REM
Pemoline (mg)
Placebo
2
4
6
30
60
90
6.8 27.7 220.8 44.0 49.8 93.8 113.0
6.5 26.7 223.5 39.2 52.3 91.5 t 22.8
7.3 24.3 235.1 38.3 56.0 94.3 110.2
3.4 21.5 237.3 31.3* 50.7 82.0 120.6
IO.8 26.5 221.3 39.8 41.0 80.8* 121.6
37.8* 30.0 212.9 29.6** 48.8 78.4* 92.3
59.4** 37.0 190.7’ 26.2** 43.7 69.9*’ 84.3C
Significance levels: *P < 0.05; **P < 0.01, Nocturnal
after the onset of sleep (P < 0.01). Stage 3 sieep was reduced with 60 and 90mg pemoline (P < 0,Ol) and total slow wave sleep (stages 3 + 4) was decreased with each dose (30 and 60 mg P < 0.05; 90mg P c 0.01). The largest dose of pemoline also led to reduced stage 2 sleep (P < 0.05) and the duration of REM sleep was decreased (P < 0.05), mainly during the second 200 min interval after the onset of sleep (P < 0.01). Latencies to REM sleep and ratios of REM to non-REM sleep were not altered. Sleep patterns of a subject with placebo and with 30,60 and 90mg pemoline are shown in Figure 2. Subjective assessments of sleep and well-being, completed the next morning, were not altered with either pemoline or pimozide, and there were no residual effects of pemoline on performance. Performance was not modified 9 hr after the ingestion of pimozide, but digit symbol substitution was impaired 11hr after 4 mg (P < 0.01) and 6 mg (P < 0.05).
sleep
The results are given in Tables 3-6. The effects of pimozide on nocturnal sleep were limited to reduced stage 3 sleep with 6mg (P < 0.05), without any change in the duration of total slow wave sleep (stages 3 + 4). The number of stage shifts during the night was decreased over the dose range (P < 0.01). Sleep patterns of a subject with placebo and with 6 mg pimozide are shown in Figure 1. Pemoline reduced total sleep time and sleep efficiency and the duration of awake activity was increased (60 mg P < 0.05; 90 mg P < 0.01). The number of awakenings was increased with 90mg (P < 0.01) and there were fewer stage shifts with both 60 and 90 mg (P < 0.01). An analysis of sleep in 200 min intervals showed that increased awake activity and stage 1 (drowsy) sleep with 60 and 90mg pemoline occurred mainly between 200 and 400 min
Table 5. Effect of drugs on duration (min) of awake + stage I (drowsy) sleep and REM sleep during 200 min intervals from the onset of sleep (means for 6 subjects) Pimozide (mg) Stage Awake + stage REM
1
Pemoline (mg)
Interval
Placebo
2
4
6
30
O-200 200-400 O-200 20+-400
13.4 14.3 32.7 58.0
17.2 14.5 28.3 68.9
7.9 15.1 31.8 54.2
9.6 11.1 33.5 59.8
17.2 11.4 35.3 58.9
90
60 9.6 47.4+* 34.6 42.5
14.8 62.2” 36.3 33.4**
Significance level: **P < 0.01. Table 6. Effect of drugs on digit symbol substitution (DSS) and choice reaction time (CRT) (means for 6 subjects) Time (hrf after ingestion 9 II
Pimozide (mg) Test
Placebo
2
DSS CRT (msec) DSS CRT (msec)
156.9 397.3 168.0 399.3
163.8 391.2 158.7 405.3
Significance levels: *P < 0.05; **P < 0.01.
4 145.3 41 I A 141.3** 423.1
Pemoline (mg) 6 144.0 409.0 145.0* 427.5
-
30
60
90
163.7 395.8 173.8 410.3
164.7 387.3 175.5 396.8
169.7 402.2 181.3 402.0
Dopaminergic transmission
415
stage
Sleep
Awake
Sta!&~and Stage 2 slow wave 1 Sleep ,
1
I
0
2
t
3
4
5
6
Steepstage Awake
7
PIMOZIDE
?I
I
I
Sh
6mg
I
Stage 1 and REM Stage 2 Slow way*
sleep
1
I
0
2
t
4
3
7
8
5
8h
Time
Fig. 1. Nocturnal sleep of a subject after placebo and after 6 mg pimozide; REM sleep is represented by the black bars and stages 3 and 4 sleep are combined as slow wave sleep. The effects of pimozide on sleep were limited and the normal pattern of REM sleep during the night was maintained.
Sleep stage
PLACEBO
Awake Stage 1 and 17
m
lm
I lull
II-
I -
IW
Stage 2 Slow wave
jw-
SlMP
P
1
0
1
2
3
4
5
6
7
8h
PEMOLlNE 30mg
Steep stage Awake Stage 1 ancl REM Stage 2 Slow wave sleep 0
f
2
3
4
5
Sleepstage
6
7
, 8h
PEMOLINE SOmg
Awake Stage 1 and REM Stage 2 Slow wave
sleep
i I
7
0 Awake
1
2
3
4
5
Sleep stage
8
7
8h
PEMOLINE gomg
Stage t and REM Stage 2 Slow wave sleep
I
’ lU b
i
i
4
i
6
b
Time
i
bh
Fig. 2. Nocturnal sleep of a subject after placebo and after 30, 60 and 90 mg pemoline; REM sleep is represented by the black bars and stages 3 and 4 are combined as slow wave sleep. There was a dose-related increase in awake activity, which led to reduced REM sleep with 90 mg, but with each dose of pemoline, REM periods occurred at similar times to those with placebo.
A. N. NICHOLSON and
416 DISCUSSION
In the present studies, modulation of central dopamine activity by pemoline, a dopamimetic drug, and by pimozide, a dopamine receptor antagonist, led to changes in the level of arousal. Pemoline increased wakefulness during nocturnal sleep and lengthened daytime sleep latencies and improved attention, while, though pimozide had little effect on overnight sleep, as shown previously in healthy individuals (Sagales and Erill, 1973, it increased the tendency to fall asleep and impaired performance during the day. These observations suggest that the influence of the dopaminergic system may vary over the sleepwakefulness continuum. It is of interest that, though both pemoline and pimozide modified the propensity to fall asleep during the day, only pemoline modulated wakefulness during sleep. The potentially activating influence of the dopaminergic system would appear to be minimal during sleep, but not necessarily maximal during wakefulness. This is consistent with studies which have shown that dopamine receptor antagonists are more effective in reducing wakefulness in rats during periods of maximum spontaneous activity when the turnover of dopamine is reported to be increased, than during periods of rest (Lemmer and Berger, 1978; Fornal, Wojcik and Radulovacki, 1982; Nagayama, Takagi and Takahashi, 1987). Daytime alertness is increased with dopamimetic agents and inhibitors of the uptake of 5-hydroxytryptamine (S-HT), and decreased with dopamine receptor antagonists, H, antihistamines and inhibitors of the uptake of noradrenaline (Nicholson and Pascoe, 1986, 1988; Nicholson, 1985) but the drugs in these groups, in similar doses, do not all lead to changes in sleep continuity. Those which increase alertness during the day also increase nocturnal wakefulness but those which decrease alertness may have a limited or be without an effect on sleep (Nicholson and Pascoe, 1986, 1988; Nicholson, Pascoe and Stone, 1985). It would, therefore, appear that some transmitters may be more concerned with the regulation of vigilance and alertness than with the underlying control of sleep and wakefulness. It is well established that drowsiness and impaired performance during the day occur with a wide range of neuroleptics. However, such effects may arise from activity other than dopamine receptor antagonism, in particular from blockade of qadrenergic and histamine H, receptors (Peroutka, UPrichard, Greenberg and Snyder, 1977; Richelson, 1984; Black, Richelson and Richardson, 1985). However, in this study reduced alertness with pimozide was related to modulation of dopaminergic transmission. Pimozide has little affinity for other neurotransmitter sites (Peroutka et al., 1977; Peroutka and Snyder, 1980) and so it is considered that sedation can arise from dopamine receptor antagonism alone.
PETAA. PASCOE
A further aspect of drugs which modulate monoaminergic transmission is their effect on REM sleep. Monoaminergic and cholinergic influences are believed to exert a reciprocal control on the appearance of REM sleep (McCarley, 1982) and drugs which alter noradrenergic or serotonergic transmission on the one hand, or cholinergic transmission on the other, disturb the balance between these factors, leading to a reduction in REM sleep, independent of any change in the duration of sleep (Sagales, Erill and Domino, 1975; Sitaram, Moore and Gillin, 1978; Nicholson and Pascoe, 1986, 1988). Decreased REM sleep with pemoline was due entirely to increased wakefulness, without any change in the ratio of REM to non-REM sleep and this is consistent with the recent analysis on the modulation of REM sleep by drugs which modify monoaminergic transmission (Nicholson et al., 1989). The absence of changes in REM sleep with pimozide and the lack of a direct effect of pemoline on REM activity clearly suggest that the dopaminergic system is unlikely to be involved directly in the elaboration of REM sleep in man. Changes in REM sleep, independent of those which arise from changes in the duration of sleep, with drugs such as chlorpromazine and nomifensine, which also modify dopaminergic transmission are, therefore, believed to be due to modulation of the activity of other neurotransmitters, particularly noradrenaline (Gaillard and Kafi, 1979; Nicholson, Pascoe and Stone, 1986). The present studies provide some evidence that the effect of drugs, which modify sleep and wakefulness, may be related to the level of activity of the central nervous system. Certainly, the level of daytime alertness can be either increased or decreased by the modulation of several monoaminergic transmitter systems, whereas sleep appears to be less susceptible to such alterations. In this way, systems may be concerned with the broad control of sleep and wakefulness and/or with the subtle regulation of vigilance. The dopaminergic system has a profound influence on the manifestation of wakefulness and vigilance but it is unlikely, like noradrenaline, 5-HT, acetylcholine, or even y-aminobutyric acid (GABA) (Belyavin and Nicholson, 1987), to be directly involved in the complex evolution of the depth of sleep or of REM sleep in man. Acknowledgements-The
authors are indebted to Dr A. Belyavin and Mrs A. Berry for statistical advice and to Miss
C. Turner
for assistance
in carrying
out the experiments.
REFERENCES
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Anscombe F. J. (1961) Examination
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