Theme : Dreams
Sleep-Wake and EEG Effects Following Adenosine A1 Agonism and Antagonism:
Similarities and Interactions with Sleep-Wake and EEG Effects Following
a Serotonin Reuptake Inhibitor in Rats
Reidun Ursin and Bjørn Bjorvatn
Department of Physiology, University of Bergen, Bergen N-5009, Norway
Abstract
Adenosine is currently being investigated as a possible mediator of a
homeostatic sleep need. Reports from different laboratories suggest that
both adenosine A1 agonists and selective serotonin reuptake inhibitors
(SSRI) increase deep slow wave sleep (SWS-2) after an interval. In this
study, the sleep-wake effects of the adenosine A1 agonist N6-cyclopentyladenosine
(CPA) and the SSRI zimeldine are directly compared in the same animals.
Since the SWS-2 increase following SSRIs may be secondary to increased
adenosine levels during the initially increased waking, it was also investigated
whether the adenosine A1 antagonist 8-cyclopentyltheofylline (CPT) would
inhibit the SWS-2 increase following the serotonin reuptake inhibitor.
Both the adenosine A1 agonist CPA and the SSRI zimeldine increased SWS-2
after an interval. Both drugs increased slow wave activity and decreased
9-20 Hz activity during SWS-2. Both the adenosine A1 antagonist CPT, zimeldine
and the two drugs combined initially increased waking and subsequently
increased SWS-2 after 2 or 4 h. All treatments increased 2-6 Hz activity
in SWS-2 after 2h. Thus, CPT did not antagonize the SWS-2 increase of
zimeldine. Based on the sleep and power spectral effects it is suggested
that the adenosine A1 antagonist potentiated the zimeldine effect, possibly
due to antagonism of adenosine A1 inhibition of serotonin release. The
data indicate that the delayed SWS-2 and slow wave activity increases
following zimeldine are not due to increased stimulation of adenosine
A1 receptors following the initial sleep loss.
Current Claim: The adenosine A1 antagonist 8-cyclopentyltheophylline
potentiates the sleep-wake and slow wave activity effects of the SSRI
zimeldine.
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Recent research has implicated adenosine as a factor in sleep mechanisms.
Several adenosine analogs have been demonstrated to increase slow wave
sleep-2 (SWS-2; delta-dominated sleep) in rats (Radulovacki et al., 1982;
1984). Adenosine A1 agonists increase delta sleep after an interval (Benington
et al., 1995; Schwierin et al., 1996) and adenosine antagonists suppress
sleep in rats (Virus et al., 1990; Schwierin et al., 1996). Adenosine
levels in the basal forebrain are higher during waking than during sleep
in cats (Porkka-Heiskanen et al., 1997), and adenosine increases in the
hippocampus towards the end of the dark period in rats (Huston et al.,
1996). Benington and Heller (1995) have postulated that extracellular
adenosine is the mediator of a homeostatic sleep need related to depletion
of glycogen stores during waking and replenishment during sleep. The mechanism
for an adenosine effect on sleep is not clear.
There is a surprising similarity between the reported sleep/wake effects
of the adenosine A1 agonist N6-cyclopentyladenosine (CPA) (Benington et
al., 1995; Schwierin et al., 1996) and the sleep/wake effects following
acute administration of serotonin reuptake inhibitors. Several serotonin
reuptake inhibitors have a biphasic effect on sleep and waking following
acute systemic administration, both in cats and rats. Initially waking
is increased, followed after 2-3 h by an increase of SWS-2 (Bjorvatn and
Ursin, 1990; Bjorvatn et al., 1992; Lelkes et al., 1994; Maudhuit et al.,
1994; Sommerfelt and Ursin, 1991; Ursin et al., 1989). Also, both the
adenosine A1 agonist CPA (Benington et al., 1995; Schwierin et al., 1996)
as well as the serotonin reuptake inhibitor zimeldine (Olsen et al., 1994)
seem to affect sleep EEG similar to the EEG effects of sleep deprivation
(Tobler and Borbely, 1990), with an increase of activity under 5 Hz and
a decrease of activity above 7 Hz. One aim of the present study was to
examine whether the sleep and EEG effects of the two treatments were comparable
when studied in the same animals. Another aim was to study whether the
delta sleep increase following a serotonin reuptake inhibitor was due
to adenosine A1 stimulation, as postulated for the CPA delta sleep increase
by Benington et al. (1995). The background hypothesis for this part of
the study was that the increased waking following the serotonin reuptake
inhibitor would increase brain adenosine, as is reported for experimental
sleep deprivation in cats (Porkka-Heiskanen et al., 1997). Therefore,
it was investigated whether the adenosine A1 antagonist 8-cyclopentyltheofylline
(CPT) would block the delta sleep increase following the serotonin reuptake
inhibitor. CPT is a selective adenosine A1 antagonist (Bruns et al., 1986).
In rats, CPT (10-20 mg/kg i.p.) increased waking and reduced SWS-2 (Virus
et al., 1990). Thus, CPT should be able to block the zimeldine induced
SWS-2 increase, if this is a consequence of increased extracellular adenosine
and increased adenosine A1 stimulation.
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Ethical evaluation
The experiment described in this article has been approved by the local
responsible laboratory animal science specialist under the surveillance
of the Norwegian Animal Research Authority and registered by the Authority.
Norway has signed and ratified The European Convention for the protection
of Vertebrate Animals used for Experimental and other Scientific Purposes
of March 18, 1986.
Animals
Twenty-three male Mol/WIST rats (Møllegaard, Copenhagen, Denmark)
weighing 250-300 g were used. The animals were housed individually in
conventional macrolone cages. They were kept on a controlled 12-hour light/12-hour
dark schedule with lights on at 0600 hours, and ambient temperature at
22o C + 1o C. The animals had access to food (RM1.(E)., SDS, England)
and water ad libitum, also during the actual recording. During surgery
animals were anesthetized with a mixture containing 0.05 mg/ml fentanyl,
2.5 mg/ml fluanizone and 1.25 mg/ml midazolam, 3 ml/kg s.c. The rats were
implanted with stainless steel screw electrodes epidurally for bilateral
fronto-frontal and fronto-parietal EEG recording (Ursin and Larsen, 1983).
Silver wires were inserted in the neck muscle for electromyographic (EMG)
recording. Temgesic (1 ml/kg s.c.) was given as a postoperative analgesic.
Drugs
Zimeldine 20 mg/kg (Astra Läkemedel AB, Sweden) was dissolved in
0.9% NaCl and injected intraperitoneally (i.p.).
N6-cyclopentyladenosine (CPA) (RBI, USA) was dissolved in the vehicle
dimethyl sulfoxide (DMSO) and injected i.p. in doses of 0.5 mg/kg (n=3)
or 1 mg/kg (n=3).
8-cyclopentyltheofylline RBI (CPT) was dissolved in DMSO and injected
i.p. in doses of 5 mg/kg (n=9) or 10 mg/kg (n=8). Injected volume was
1.5 ml/kg (ca. 0.5 ml per animal) for all injections.
Experimental design
Three weeks were allowed following surgery for recovery and adaptation
prior to the experiments. The animals were adapted to the recording environment
during the last week before the experiments started, with cables attached
for at least three days, several hours per day.
CPA compared with zimeldine: A baseline recording was followed by recordings
following 20 mg/kg zimeldine, or CPA 0.5 mg/kg (n=3) or 1 mg/kg (n=3),
or vehicle alone, in a balanced order design.
CPT plus zimeldine: Each of the 17 rats went through four experimental
conditions, with two i.p. injections given 15 min apart, in a balanced
order design: Saline + vehicle; zimeldine + vehicle; saline + CPT 5 mg/kg
(n=9) or 10 mg/kg (n=8); and zimeldine + CPT (5 or 10 mg/kg). Six rats
were recorded for 6 h. Since many effects were still present in the 6th
hour following drug administration, 11 rats were recorded for 8 h to study
effects 7-8 h following drug administration.
Recording and sleep scoring
The animals in their home cages (Gabbia Plastic Cage, Tecniplast, Italy,
measuring 425 x 266 x 150 mm), with water and food ad libitum, were placed
into sound-attenuated recording chambers (430 x 280 x 620 mm) with light
(15-W electric bulb) and ventilation. Ambient temperature was 24-28o C
during recording. Free movement was permitted due to a flexible recording
cable and a rotating connector fixed to a moveable arm outside the chamber.
Recording started at 08.30 h ± 15 minutes.
Fronto-frontal (FF) and fronto-parietal (FP) EEG and EMG signals were
recorded with paper velocity 10 mm/second. FF EEG was high-pass filtered
with a 3 Hz half-amplitude filter (6 dB/octave) and low-pass filtered
with a 35 Hz half-amplitude filter (12 dB/octave), and FP EEG was high-pass
filtered with a 1 Hz half-amplitude filter (6 dB/octave) and low-pass
filtered with a 35 Hz half-amplitude filter (12 dB/octave). The difference
in filter characteristics was chosen to facilitate visual-spindle detection
in the FF lead. EEG sensitivities ranged from 50-150 µV/cm (FF)
and 100-300 µV/cm (FP). The amplifiers had a 50 Hz notch filter
to eliminate influence from the AC frequency. EEG and EMG signals were
also digitized on-line with a sampling frequency of 128 samples per second,
A/D converted (12-bit Keithley 575 A/D converter) and stored.
Off-line the two EEG signals were subjected to a fast Fourier transform
(FFT) using 2-sec epochs, giving half-Hz bins from 0-64 Hz. Each bin was
named after its lower limit. The 0 Hz and 60.5-64.0 Hz bins were discarded.
The bins from 20.5-60.0 Hz were collapsed into a single High bin. EMG
was analyzed off-line to obtain total variance.
Sleep and waking were scored in 10-sec epochs following a semiautomatic
procedure employing EEG power spectral values in the delta, theta and
sigma (11-16 Hz) bands and EMG variance (Neckelmann et al., 1994), based
on earlier published criteria (Ursin and Larsen, 1983; Neckelmann and
Ursin, 1993), and validated against visual scoring (Neckelmann et al.,
1994). Stages scored were waking, slow wave sleep-1 (SWS-1) with spindles,
slow wave sleep-2 (SWS-2) with spindles and delta activity, and REM sleep.
Spindle and delta thresholds were determined in the baseline recording
and remained the same for scoring of the drug condition records. Scoring
epoch length was 10 sec, which means five 2-sec FFT epochs within each
scoring epoch. This was done to take into account the temporal aspect
important in visual EEG scoring, and was performed following a set of
hierarchical rules as described by Neckelmann et al. (1994).
EEG power spectral analysis
Power spectra were computed for the six rats in the CPA and zimeldine
experiment and for the 17 rats in the CPT plus zimeldine experiment for
6 hours of recording.
A computer program selected all 2-sec FFT data from waking, SWS-1 and
SWS-2. Artifact epochs were excluded from the analysis. The selected FFT
data were averaged in 2-hour periods for each stage separately. Since
REM sleep was almost absent following zimeldine administration, spectral
values from this stage were not investigated.
Statistics
Data were analyzed with Statsoft Statistica, using ANOVA for overall
comparison. Significant effects were further evaluated with ANOVAs and
t-tests. Dose, treatment, stage and 2-h period were entered in the overall
analyses. Significance was accepted at p < 0.05.
In the analysis of the power spectral data, absolute power densities
are not very suitable for visualization of drug effects, because the interindividual
variation is considerable and the absolute values of the lower frequencies
are several orders of magnitude higher than those of the higher frequencies.
For each rat, the power values of the drug conditions were therefore expressed
relative to control. These relative values were log-transformed prior
to the statistical analysis to reduce the effects of non-gaussian distribution.
The interindividual averages of the log-transformed relative power densities
were retransformed before plotting to give a linear axis (Bjorvatn and
Ursin, 1994; Dijk et al., 1989). The non-parametric Wilcoxon signed rank
test was used for the analysis of these data.
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Figure 1
Figure 2
Figure 3
Figure 4
CPA compared with zimeldine
Sleep and waking stages. There was no significant difference between baseline
and vehicle experiments (MANOVA, Rao's R (3,3) = 0.62, p = 0.64) and the
rest of the statistics were run with the vehicle experiment as control.
Overall ANOVA showed no effect of CPA dose (F (1,4) = 0.76, p = 0.43).
There was no overall effect of treatment (F (2,8) = 2.97, p = 0.11), but
there was a significant interaction between treatment, stage and 2-h period
(F (12,48) = 9.41, p < 0.0001). Since there was no effect of CPA dose,
data from the two groups were pooled for the post hoc analyses. Post hoc
t-tests indicated sleep-wake changes as illustrated in Fig. 1. Waking
was increased and sleep decreased in the first 2-h period following administration
of both zimeldine and CPA. SWS-2 was increased in the second 2-h period
following zimeldine. The values following CPA in the second and third
2-h period did not reach significance (p < 0.06), however SWS-2 added
over the two 2-h periods was significantly increased (p < 0.05). The
two treatments had significantly different effects only on REM sleep (F
(1,5) = 9.88, p < 0.05). REM sleep was reduced following zimeldine
throughout the recording, following CPA only in the first 2-h period (Fig.
1).
EEG power spectrum. Fig. 2 shows fronto-parietal EEG power spectrum in
SWS-2. Following CPA there was an increase in slow wave activity (0.5-2.5)
Hz during the first and second 2-h period, following zimeldine the increase
was in the 3-4.5 Hz range and particularly in the second 2-h period. Following
zimeldine there was also a reduction of frequencies above 7 Hz; this was
present but less conspicuous following CPA.
CPT and zimeldine combined
Sleep and waking stages. Overall ANOVA showed no effect of CPT dose (F
(1,15) = 0.02, p = 0.96). There was an overall effect of treatment (F
(3,45) = 19.95, p < 0.0001) and an effect of sleep stage (p< 0.0001).
Since there was no effect of CPT dose, data from the two groups were pooled
for the post hoc analyses and figures. The sleep and waking stages for
the 17 rats recorded for 6 h are shown in Fig. 3. Eleven of the animals
were recorded for 8 h, data from hours 7-8 in these animals are also shown
in Fig. 3.
There was an effect of CPT treatment (F (2,32) = 19.3, p < 0.0001)
and an interaction of treatment, stage and 2-h period (F (12,192) = 35.5,
p < 0.0001). There was also effect of zimeldine treatment (F (2,32)
= 21.3, p < 0.0001) and an interaction between treatment, stage and
2-h period (F (12, 192) = 41.7, p < 0.0001). A comparison of CPT versus
CPT plus zimeldine effects showed a significant difference between these
treatments (F (1,16= 19.5, p < 0.001). The difference between zimeldine
recordings and zimeldine plus CPT recordings did not reach significance
(p = 0.06) but there was a significant interaction between treatment,
stage and 2-h period (F (6,96) = 26.7, p < 0.0001).
Waking. Both zimeldine, CPT and the combination zimeldine + CPT induced
a large increase of waking during hours 1-2 following injections (Fig.
3). During hours 3-4 waking was increased by over 100% by the combination,
less, but still significantly increased by zimeldine alone and CPT alone.
Slow wave sleep. There was a decrease of SWS-1 in the first and second
2-h periods (hours 1-4) following all treatments, particularly following
the combination zimeldine plus CPT. During the third 2-h period there
was still a large decrement following the drug combination, and a smaller
decrease following CPT. In the fourth 2-h period the values were back
to control level (Fig. 3). SWS-2 values were considerably reduced during
the first 2-h period by all treatments (Fig. 3). However, in the second
2-h period there was a significant increase following zimeldine alone,
while SWS-2 following CPT and zimeldine plus CPT was not different from
control level. In the third 2-h period, the CPT treatment gave a small
but significant increase (p < 0.01), while the combination zimeldine
plus CPT gave a 100% increase in SWS-2 compared to control level (p <
0.0001), and an almost 50% increase in the CPT-alone condition (p <
0.0001). The difference between the combination and zimeldine alone was
also significant in the third 2-h period (p < 0.0001). During the fourth
2-h period there was still a slight elevation of SWS-2 following the combination,
while levels following zimeldine and CPT alone were back to control level
(Fig. 3).
Corresponding to the changes in SWS-1 and SWS-2, total SWS was reduced
in the first 2-h period following all treatments. In the second 2-h period,
only the zimeldine-CPT combination reduced total SWS. In the third 2-h
period there were small but significant increases following all three
treatments, in the fourth 2-h period only following the combination (Fig.
3).
REM sleep was almost abolished during the first 2-h period following
both zimeldine, CPT and combination treatments (Fig. 3). In the second,
third and fourth 2-h period values were still very low following zimeldine
and the combination. REM sleep following CPT was slightly but significantly
reduced in the second 2-h period, in the third and fourth 2-h period it
was not different from control value.
EEG power spectrum. Both zimeldine and CPT increased slow wave activity
in SWS-2 in the 2.5-6 Hz range (Fig. 4). While zimeldine decreased 9-20
Hz activity, this was not seen following CPT, rather, there was a slight
increase in some bins. The most conspicuous finding was the power increase
in the 2-6 Hz bins following the combination CPT plus zimeldine, particularly
in the second 2-h period, but also in the third 2-h period and in the
total 6-h period (Fig. 4). Following the combination there was less reduction
of 9-20 Hz activity than following zimeldine alone.
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Zimeldine and the adenosine A1 agonist CPA both increased waking and subsequently
increased SWS-2. Both compounds reduced REM sleep, however, zimeldine
considerably more than CPA, and this was the only clear difference between
the sleep/wake effects of the two drugs. Following both compounds EEG
slow wave activity increased particularly in the second 2-h period, the
frequencies following zimeldine being higher (3-4.5 Hz) than following
CPA (0.5-2.5 Hz). Decrease in the power of frequencies between 8-9 Hz
and 20 Hz was present following both treatments. It has been argued (Benington
et al., 1995; Schwierin et al., 1996) that CPA effects on sleep mimic
effects of sleep deprivation, with an increase of slow wave activity below
4-5 Hz and a decrease of frequencies above 10 Hz (Tobler and Borbely,
1990). In the present study both CPA and zimeldine seemed to have such
effects, although the frequency spectrum of the increased slow wave activity
was slightly different for the two compounds.
For CPA, it has been demonstrated that the initial waking effect may be
secondary to a reduction in body temperature (Benington et al., 1995).
When this effect was eliminated by warming the animal, the slow wave increase
appeared earlier (Schwierin et al., 1996). There is no temperature change
following zimeldine (Bjorvatn et al., 1996). The initial waking following
zimeldine administration may be a consequence of other serotonergic effects
incompatible with sleep (see Bjorvatn and Ursin, 1990), e.g., a direct
serotonergic effect on the thalamus, reducing spindle oscillations and
thereby sleep (Lee and McCormick, 1996). According to Benington and Heller
(1995), adenosine operates as a feedback signal in sleep homeostasis,
stimulated by depletion of cerebral glycogen reserves. The manifestation
of the sleep need is postulated to appear as increased EEG slow wave activity
following stimulation of the adenosine A1 receptor. It has been demonstrated
that prolonged wakefulness increases extracellular adenosine in the basal
forebrain of cats, the values declining towards baseline during 3-h recovery
sleep (Porkka-Heiskanen et al., 1997). Also, during spontaneous sleep-wake
cycles these authors found lower adenosine levels in SWS than during waking.
Adenosine increases in the hippocampus towards the end of the dark period
in rats (Huston et al., 1996). The mechanism by which adenosine may affect
sleep is not clear. Adenosine perfusion both into the basal forebrain
and the lateral dorsal tegmental nucleus decreases waking (Portas et al.,
1997). Adenosine sleep effects may be direct on central nervous system
neurons or may be mediated via effects on neurotransmitter release (see
Brundege and Dunwiddie, 1997) or via receptor effects (Ferré et
al., 1996).
The background for the SWS-2 and slow wave activity increases following
zimeldine and other serotonin uptake inhibitors (Ursin et al., 1989; Sommerfelt
and Ursin, 1991; Olsen et al., 1994; Lelkes et al., 1994; Maudhuit et
al., 1994) is not clear. The similar effects of zimeldine and CPA in the
present study may indeed suggest that the SWS-2 increase following zimeldine
is a consequence of increased adenosine levels during the initial sleep
loss (Porkka-Heiskanen et al., 1997) and therefore increased adenosine
A1 receptor stimulation (Benington et al., 1995). If so, it should be
eliminated by an adenosine A1 antagonist.
When zimeldine was administered in combination with the A1 antagonist
CPT, however, the increase of SWS-2 was still present, only postponed
to the third 2-h period following administration (Fig. 3). There was also
increased slow wave activity in SWS-2 in the second and third 2-h period
(Fig. 4) following the combination. Thus the zimeldine-induced SWS-2 and
slow wave activity increases were not blocked by the A1 antagonist, the
sleep increase was postponed and the slow wave activity increased. The
present data, then, do not support the idea that the zimeldine SWS-2 and
slow wave activity effect were a consequence of increased extracellular
adenosine and A1 receptor stimulation following the initial waking increase.
The adenosine A1 antagonist CPT administered alone increased waking during
the first two 2-h periods following administration. This indicates a biological
effect of CPT over at least 4 hours, in agreement with Virus et al. (1990),
who reported increased waking over a 6-h period following 10 mg/kg CPT.
SWS-1 and REM sleep were still reduced during the second 2-h period while
SWS-2 was similar to control. In the second 2-h period there was an increase
of EEG slow wave activity in SWS-2 (Fig. 4). This finding is consistent
with the data of Schwierin et al. (1996). They employed a high dose of
the A1 antagonist caffeine and reported an initial sleep decrease succeeded
by increased slow wave activity in the second 2-h period following administration.
Thus, in theirs as well as in our study, slow wave activity following
the adenosine A1 antagonist was increased while sleep was still decreased.
The findings of increased slow wave activity 2-4 h following A1 antagonists,
while there is still a drug-induced sleep reduction, are surprising. The
findings might be due to a buildup of sleep drive during the preceding
waking period. However, the effect came too soon and following a too small
sleep loss to be a compensatory response. Tobler and Borbely (1990) found
no significant increase of slow wave activity after a 3-h total sleep
deprivation. It is possible that adenosine A1 antagonists may increase
the rate of buildup of sleep drive during the drug-induced waking. However,
Schwierin et al. (1996) found a smaller rise of EEG power density following
caffeine-induced waking than following the same length of non-drug sleep
deprivation. Also, the frequency distribution of the slow wave activity
following CPT (2.5-6 Hz) was different from the frequency spectrum of
the slow wave activity following sleep deprivation (Tobler and Borbely,
1990; Franken et al., 1991). In any case, if the manifestation of increased
sleep drive is mediated through adenosine A1 receptors, one should have
expected the A1 antagonists to block this manifestation.
The sleep-wake effects of CPT and zimeldine were surprisingly similar,
as were the changes in EEG slow wave activity following their administration.
The combination of zimeldine and the A1 receptor antagonist seemed to
accentuate the zimeldine effects, both the initial waking and the delayed
SWS-2 increase. Also, the combination augmented the slow wave activity
effects of zimeldine, with a 2-6 Hz increase following zimeldine and a
2-7 Hz increase following the combination.
A prominent effect of adenosine in the brain is its ability to inhibit
the release of neurotransmitters. These effects are reported to be mediated
by presynaptic A1 receptors in most systems and may be due to inhibition
of calcium entry into nerve terminals (see Brundege and Dunwiddie, 1997).
Both adenosine and the A1 agonist CPA perfused into the dorsal hippocampus
of rats decrease extracellular 5-HT levels, while CPT and caffeine increase
hippocampal extracellular 5-HT (Okada et al., 1997). A possible explanation
for the similarities between the A1 receptor antagonist CPT and zimeldine,
and the potentiation of effects by the combination of the drugs, may be
that the A1 antagonist blocks an adenosine inhibitory effect on 5-HT release,
leading to increased release. Another possibility is blockade of the inhibition
of raphe cells mediated via A1 receptors. An adenosine transporter blocker
infused into the dorsal raphe nucleus increased REM sleep (Strecker et
al., 1997), possibly because of inhibition of serotonergic cells, thereby
disinhibiting REM sleep-generating mechanisms (McCarley et al., 1995).
Both caffeine (Schwierin et al., 1996) and CPT tended to increase 8-20
Hz activity, and the combination zimeldine-CPT reduced these frequencies
less than zimeldine alone. Activity in these frequencies tends to be low
in the beginning of the light period and are high in the dark (Trachsel
et al., 1988). As rats are nocturnal animals this effect of the drugs
suggests a tendency towards increased activation, which would be expected.
The effects of zimeldine as a selective serotonin reuptake inhibitor
are considered mainly due to increased serotonin at serotonergic nerve
terminals and are thus dependent on the physiological activity of the
serotonergic neurons. Zimeldine has no pharmacological receptor effects
on its own (Hall and Ögren, 1981). It is thus likely that the zimeldine
effects on slow wave activity and SWS-2 are related to increased serotonergic
transmission. In the thalamus, modulation by serotonin in vitro may increase
the frequency of intrinsic oscillations in thalamocortical neurons, and
also tend to reduce the cells' ability to oscillate (see McCormick and
Bal, 1997). However, 5-HT1A receptor stimulation may under certain conditions
increase SWS-2 and slow wave activity. Systemic administration of the
5-HT1A receptor agonist 8-OH-DPAT produces a delayed SWS-2 increase too
large to reflect a rebound after the initial waking period following this
drug (Bjorvatn et al., 1997). In vitro stimulation of 5-HT1A receptors
on basal forebrain cholinergic neurons increases rhythmic burst activity
mediated by low-threshold calcium spikes (Khateb et al., 1993), and microinjection
of serotonin into the nucleus basalis in vivo in rats increases slow wave
activity (Cape and Jones, 1998). Jouvet (1995) has suggested that release
of serotonin during waking may initiate a cascade of genomic events in
hypnogenic neurons in the preoptic area, thus linking serotonin to a homeostatic
regulation of slow wave sleep.
Adenosine A1 receptor modulating drugs may also interact with dopamine
D1 receptor function both in the basal ganglia, the medial prefrontal
cortex and in the nucleus accumbens (Ferré et al., 1996). Dopamine
release in the nucleus accumbens is in part regulated by serotonergic
neurotransmission (Yoshimoto and McBride, 1992). Firing rate in the nucleus
accumbens is associated with the level of cortical arousal, being higher
in waking and REM sleep than in NREM sleep (Callaway and Henriksen, 1992).
Thus the effects on waking and on the higher EEG frequencies by CPT and
its potentiation by zimeldine may possibly be mediated via increased dopaminergic
activity in the nucleus accumbens.
In conclusion, the present data indicate that the delayed SWS-2 and slow
wave activity increases following zimeldine are not due to increased stimulation
of adenosine A1 receptors following the initial sleep loss. Instead, the
data suggest that the observed potentiation of the zimeldine sleep/waking
and slow wave effects by the adenosine A1 antagonist CPT may be due to
antagonism of adenosine's ability to inhibit serotonin release, and/or
to interactions with dopaminergic activity.
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The study was supported in part by The Research Council of Norway.
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