According to clinical investigations, sleep
deprivation (of REM phase) may have an
antidepressive therapeutic effect. Hence, it
seemed interesting to compare, applying
pharmacological tests, the effects of sleep
deprivation with the effects of chronically
administered antidepressant drugs. We have
demonstrated in our previous studies that REMD
elicits in rats changes similar to those
observed after chronic administration of
antidepressants and electroshocks. Like
imipramine, desipramine or electroshocks, REMD
reduced density of 3H-dihydroalprenolol and
3H-imipramine binding sites in the rat cerebral
crtex and inhibited clonidine-induced sedation.
Taking into account the fact that
catecholamines and serotonin (5-HT) are
essential for sleep and that antidepressive
therapy (whether with antidepressants or with
electroshocks) affects catecholaminergic and
5-HT-ergic systems, we decided to check whether
the behavioral response to stimulation of these
systems is altered in rats deprived of REM
sleep.
Accordingly, the influence of REMD on
apomorphine (APO), dopamine (DA)-agonist, was
studied. Stereotypy and aggressive behavior
served as the criteria of catecholaminergic
activity; the activity of 5-HT-ergic system was
evaluated by measuring head twitch response
induced in rats by administration of
quipazine.
REM deprivation : Male Wistar rats
(200-250 g) were used for experiments. REMD was
achieved tising the water tank procedure. For
experiments, two groups of animals were studied
in parallel: in the first, the control group,
rats werc kept (for 48 h) individually in dry
transparent cages; in the second group, REMD was
achieved by placing the animals on small
platforms of 6 cm diameter surrounded by
water-this condition permitted the occurrence of
slow wave sleep but not of REM sleep. Rats were
deprived of REM sleep for 48 hr, beginning at 10
a.m. All rats-control and REM deprived animals
had unlimited access to food and water.
Stereotypy and aggressiveness
Immediately or 96 hr after completing of a 48
hr lasting REMD, rats were placed individually
in wire mesh cages (20x2Ox23 cm), injected with
APO 0.5 mg/k-g (dissolved in water) to assess
stereotypy, or with a dose of 5 mg/k-g SC to
test aggressive behavior (10 min after the
injection of APO the animals were paired).
Stereotypy was assessed 30 min after APO
injection tising the scale 0-4. Fighting
behavior was defined when both rats assumed
upright posture standing on their hind legs, or
when the animal forced its partner to assume
different patterns of submissive posture. The
number of rat pairs showing continuous or
incidentally interrupted fighting was recorded
and included in Table 1.
Head twitches : Immediately or 48, 72
and 96 hr after completing of a 48 h lasting
REMD, rats were placed individually in wire mesh
cages and, just after injection of quipazine 10
mg/kg IP, head twitches were recorded for 30
min. Quipazine hydrochloride was dissolved in
0.9% NaCl.
RESULTS
REMD did not affect the stereotypy induced by
APO neither immediately after completing of
REMI) nor 96 hr later (data not shown).
APO (5 mg/kg) apparently did not induce
aggressiveness in control rats. A strong
aggressive behavior after APO was observed in
REMD animals when APO was given immediately but
not 96 hr after completing of a 48 hr REMD
(Table 1). Fighting occurred just after the
pairing and persisted incessantly or with short
breaks for about 1.5 hr.
As is shown in Fig. 1, REMD reduces the
number of quipazine-induced head twitches if
quipazine is administered immediately after
completing of deprivation. However, if
administration of quipazine is postponed for
some time (48, 72, 96 hr) after completion of
deprivation, the opposite effect is observed,
ie. quipazine incrcases the number of head
twitches in REMD animals. This effect is
statistically significant for quipazine
administered after a delay of 96 hr.
DISCUSSION
In this study, we have confirmed the fact,
noted by other authors, of increase by REMD of
APO-induced aggression. We have also found that
REMD changed the response to serotonergic
stimulation, which was quantified by the number
of quipazine-induced head twitches.
In the mechanism of pharmacologically induced
aggression an important role is attributed to
the DA-ergic and noradrenergic systems. The
potentiation of APO induced aggression may be
due to the enhanced function of the
catecholaminergic system. It seems, however,
that a 48 hr REMD potentiates APO-induced
aggression by affecting the noradrenergic rather
than the DA-ergic system, since REMD did not
modify APO-induced stereotypy. This involvement
of the noradrenergic system is further
implicated by the results of our previous
studies where we demonstrated that REMD
abolished clonidine-induced sedation. Similar
results, i.e., potentiation of APO-induced
aggression, were observed by Tufik, though they
observed, in addition, the enhancement of
APO-induced stereotypy. From these results, they
suggested that after REMD the supersensitivity
of DA receptors occurs. They used, however, a
longer period of REMD than we did; thus, it is
possible that a 48 hr REMD is not sufficient to
induce alterations in the DA-ergic system.
The influence of REMD on aggression is
similar to the effect of other antidepressive
treatments. We have demonstrated previously that
chronic administration of antidepressants
potentiates APO-induced aggression or footshock
induced aggression and that this effect was
sustained for a considerable period of time
(unpublished data). In the case of REMD, the
potentiation of aggression was noticeable
immediately after completion of 48 hr lasting
deprivation: 96 hr later this effect
disappeared. We think, that longer lasting REMD
would induce more durable changes and that the
potentiation of aggression would continue for a
longer time, as it does after treatment with
antidepressants. Recently, Hicks et al. have
shown that REMD increased aggression in rats in
a dose-dependent manner: the effect of 4 days
REMD was more pronounced and longer lasting than
the effect of 2 days REMD.
In the second series of experiments, we have
demonstrated that REMD modifies the response to
the stimulation of 5-HT-ergic system: REMD
reduced the beliavioral response (head twitches)
to quipazine if the drug was given immediately
after completion of REMD, after a 96 hr delay,
the head twitch response to quipazine was
increased.
The similar pattern of alterations in the
response to 5-HT-ergic stimulation was detected
after treatment with antidepressants: chronic
treatment with amitriptyline or imipramine
inhibited head twitches induced in mice by
5-methoxydimethyltryptamine if this agent was
given 1 hr after the last dose of
antidepressant, after a 48 hr delay, the number
of head twitches was increased. We have also
reported an increase in behavioral response to
5-hydroxytryptophan after a chronic treatment
with mianserin, danitracen and amitriptyline.
The increased response of the 5-HT-ergic system,
which is observed after REMD, suggests the
occurrence of supersensitivity. De Montigny and
Aghajanian found this phenomenon after prolonged
treatment with antidepressants. They showed that
various antidepressants given chronically
potentiated the response of forebrain neurons to
electrically applied 5-HT. Recently, Vetulani et
al. have concluded that electroconvulsive
treatment leads to the supersensitivity of the
5-HT-eigic system in rats, since they
demonstrated an increase in the density of
3H-spiperone-labelled 5-HT receptors and
potentiation of quipazine or 5-HTP-induced head
shakes in animals treated with
electroshocks.
The results obtained in this study indicale
that in rats REMD induces changes in
noradrenergic and 5-HT-ergic systems similar to
those obtained with other antidepressive
treatment, e.g., chronic administration of
antidepressants or electroshocks. This
similarity indicates a potential application of
REMD in the therapy of depression.
