Does REM
sleep deprivation induce subsensitivity of
presynaptic dopamine or postsynaptic
acetylcholine receptors in the rat
brain?
Sérgio Tufik, Lanfranco R.P.
Troncone, Sandra Braz, Armando R. Silva-Filho
and Beatrice G. Neumann
Department of
Psychobiolology, Escola Paulista de Medicin,
Sâo Paulo, Brazil
Introduction: Several studies have
demonstrated that rats submitted to REM
sleep deprivation (REMSD) show an augmented
response to dopamiergic agonists as indicated by
an intensification of agressiveness, stereotypy
and rearing (Tufik et al., 1978; Mogilnicka,
1981; Trotta, 1984). Such a response is not due
to a modification in dopamine (DA) turnover or
levels (Ghosh et al., 1976), since it has been
demonstrated that animals treated with L-DOPA
and injected with apomorphine fail to show
aggressive behavior (Tufik, 1981a). On the other
hand, REMSD rats pre-treated with a
methyl-para-tyrosine continue to show the same
intense response to DA agonists, suggesting that
presynaptic mechanisms are not of prime
importance for the appearance of this augmented
response induced by REMSD (Tufik, 1981a).
In order to further our knowledge concerning
the effects of REMSD on presynaptic DA receptors
and postsynaptic acetylcholine (ACh) receptors,
we decided to study a specific behavior,
namely yawning, which can be elicited
either by stimulation of DA autoreceptors or by
cholinomimetic agents (Mogilnicka
and Klimek, 1977; Urba-Holmgren
et al., 1977), in REMSD rats.
Several reports in the literature, suggest
that morphine at low doses stirnulates DA
autoreceptors (Laschinski et aL, 1984; Yarbrough
et al., 84). At low doses apomorphine produces
sedation and elicits yawning in rats (Mogilnicka
and Klimek, 1977). Recent findings have
suggested that, on the other hand, yawning would
be produced by stimulation of a particular,
supersensitive, group of D2 receptor (Serra
et al., 1986). Other researchers have
proposed that yawning would be produced by
combined stimulation of both D1 and D2 receptors
(Morelli et al., 1986).
It has been demonstrated that intense
yawning is produced by drugs that enhance ACh
transmission, including pilocarpine and
physostigmine (Ushijima
et al., 1984b). A role of ACh transmission
in this behavior is made plausible by the fact
that yawning produced by apomorphine can be
blocked by neuroleptics (Mogilnicka and Klimek,
1977) and by ACh receptors blockers (Ushijima et
al., 1984b). Furthermore, the latter authors
showed that yawning produced by pilocarpine or
physostigmine was not abofished by neuroleptics
but by ACh antagonists.
The literature suggests the existence of
a cholinergic link preceded by a dopaminergic
link in the elicitation of yawning behavior.
Stimulation of doparnine autoreceptors
interrupts doparninergic transmission, thus
freeing the cholinergic system and consequently
eliciting yawning behavior. However, this
hypothesis might be challenged because we cannot
induce yawning merely by blocking the DA system
with neuroleptics, despite the fact that these
drugs potentiate yawning induced by
physostigmine (Berendsen and Gower, 1983).
Furthermore, a recent report (Morelli et al.,
1986) suggests that yawning can be produced by
an interaction between D1 and D2 receptors.
It was reported that (-)-3PPP, an agonist of
presynaptic and antagonist of postsynaptic DA
receptors (Arnt et al., 1983, Koch et al.,
1983), does not produce yawning while reserpine
was able to elicit yawning 24 h after its
administration but not after 6 and 12 h, when DA
depletion and impairment of DA transmission are
known to be maximal. On the other hand, this
reserpine-induced yawning was blocked by
sulpiride and amethyl-p-tyrosine (Guldberg and.
Broch, 1971). These findings led Serra et al.
(1986) to suggest that a different population of
D2 receptors, more sensitive than the normal D2
receptors, probably mediates yawning produced by
these doparninergic agent.
In the present work the REMSD animals showed
a reduced number of yawns in response to
apomorphine, pilocarpine or physostigmine. These
drugs however produced different effects on the
dose-response curves. Neither pilocarpine nor
apomorphine could produce the same amount of
yawns in REMSD and cantrol animals even in
higher doses, as indicated by a lowering of the
experimental curve. The curve obtained for
physostigmine was quite different, with a shift
toward the right. This suggests that REMSD
results in the blockade of apomorphine- and
pilocarpine-induced yawning through a mechanism
which resembles a non-competitive process.
In the case of physostigmine, such a
mechanism resembles a competitive process.
Although both drugs are acetylcholine receptor
agonists, they have different modes of action:
pilocarpine is a direct agonist of the muscarmic
receptor whereas physostigmine is an inhibitor
of acetylcholinesterase. Conformational changes
of the muscarimic receptor in the brain,
produced by REMSD, might have diminished the
affinity of pilocarpine for the acetylcholine
receptor which would explain an overall blockade
of pilocarpine-induced yawning. Such was not the
case with physostigmine: the several fold
increase of acetylcholine in the synaptic cleft
would overcome the antagonism of REMSD
completely if one considers that the affinity
for its receptor is not diminished.
The results of the present study could
suggest that the process of REMSD may lower the
responsivity of the DA and/or the cholinergic
system to induce yawning. One miht suggest
that REMSD would only decrease acetylcholine
receptor sensitivity if the dopaminergic
mechanisin depends on cholinergic transmission.
On the other hand, rats treated for long periods
with haloperidol show an augmented
responsiveness to DA agonists (as measured by
stereotypic and aggressive responses) during the
withdrawal phase. REMSD rats show the same
hyperesponsiveness to DA agonists and this is
further potentiated if a single dose of
haloperidol is administered during the
deprivation period (Tufik, 1981b). During
withdrawal after long-term haloperidol, rats
show much less yawning when tested with
apomorphine and physostigmine, but their
responses to pilocarpine are not altered
(Ushijima et al., 1984a).
This suggest that REMSD and long-term
haloperidol share common characteristics but are
not identical in terms of effects on various
brain receptors.
Taking the above findm-gs into account, it
is plausible that either REMSD or chronic
administration of haloperidol, while producing
supersensitivity of the receptors that mediate
stereotypy would block yawning produced by low
doses of apomorphine. According to the present
hypothesis yawning might be considered to
indicate a low degree of arousal, mediated by
the activavation of the most sensitive
population of DA receptors proposed by Serra et
al. (1986). Further of DA transmission (REMSD
and haloperidol withdrawal) might progress to
full arousal, exploratory behavior, stereotyped
sniffing, licking and yawning. This hypothesis
offers a logical explanation for the fact that
yawning and stereotypy are mutually exclusive.
It could also explain the reduction by either
REMSD or haloperidol withdrawal of yawning
elicited by apomoorphine. Nevertheless, we did
not observe stereotypy REMSD animals during the
present experiments although exploratory
behaviors of the rats have reduced their
yawning.
As to possible mechanisms, it sho recalled
that yawning behavior can be produced by
intracerebroventricular injection of ACTH (Gessa
et al., 1966; Rees et all 1976) other peptides
(Yamada and Furukawa 1981) Considering that
REMSD is itself a stressful procedure, it is
conceivable that during this this treatment,
there is an intense and prolonged production and
release of ACTH which could eventually decrease
the sensitivity to ACTH. As a consequen ce, one
would observe a reduction in the number of yawns
induced by any other drug tested after REMSD,
since this behavior seems to depend on an entire
chain of systems (ACTH-ACh-DA) for its
production. These hypotheses await further
experimental work.
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Does REM sleep deprivation induce subsensitivity
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acetylcholine receptors in the rat brain?
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215-219
