Department of Psychobiology,
Escola Paulista de Medicina, Sao Paulo,
Brasil
Abstract : Paradoxical sleep (PS)
deprivation has been suggested to induce
supersensitivity of postsynaptic dopamine (DA)
receptors and subsensitivity of acetylcholine
(ACh) receptors. Yawning behavior is reduced
after PS deprivation and is believed to result
from an interaction between ACh and DA systems.
Concomitant treatment of PS deprived animals
with DA agonists reverses PS deprivation effects
on stereotypy and aggressiveness. To examine
this possibility on yawning behavior, rats were
treated, during the deprivation period, with
atropine, methamphetamine, haloperidol or
distilled water. Following PS deprivation, rats
were injected with apomorphine or pilocarpine
and number of yawns was recorded. Atropine
increased yawning of PS deprived rats induced by
pilocarpine, but not by apomorphine. Treatment
with methamphetamine and haloperidol did not
change PS deprivation effect on pilocarpine- and
apomorphine-induced yawning. The data suggest
that reversal of PS deprivation-induced yawning
inhibition is mediated distinctly by both
acetylcholine and dopamine systems.
The functional significance of yawning is
still unknown, although this behavior has been
studied for the last 3 to 4 decades. Yawning can
be elicited by several cholinergic (AChergic)
agonists, by low doses of dopaminergic (DAergic)
agonists, and by polypeptides such as a-MSH and
ACTH. Moreover, Gower et al. showed that
serotonin, histamine, and noradrenaline systems
play a role in modulating this behavior.
Yawning has been suggested to result from a
balance between DAergic and AChergic systems.
This conclusion is based on a study by Yamada
and Furukawa, who showed that scopolamine, a
cholinoceptor antagonist, inhibits apomorphine-,
pilocarpine-, and physostigmine-induced yawning.
The neuroleptic fluphenazine, however, does not
modify pilocarpine-induced, but increases the
number of physostigmine induced yawning. In
addition, sulpiride, a D2 dopamine (DA) receptor
blocker, inhibits apomorphine-induced, but not
physostigmine-induced yawning. Thus, yawning
appears to be mediated by inhibition of DAergic
system and activation of AChergic system.
Paradoxical sleep (PS) deprivation induces
several changes on human's and rat's behavior,
such as increased apomorphine-induced stereotypy
and aggressive behavior in rats, and improvement
of endogenous depression symptoms in humans. It
is proposed that these effects are a consequence
of postsynaptic DA receptors supersensitivity,
and presynaptic DA receptors and postsynaptic
acetyicholine (ACh) receptors subsensitivity. PS
deprivation also inhibits yawning elicited by
apomorphine, physostigmine, and
pilocarpine.
Haracz and Tseng showed that DA receptor
supersensitivity resulting from neuroleptic
treatment is attenuated by an acute dose of
amphetamine. In addition, treatment of PS
deprived animals with amphetamine and L-dopa
results in reversal of deprivation effects on
apomorphine-induced stereotypy and
aggressiveness; behaviors that occur as a
consequence of postsynaptic DA receptor
supersensitivity.
Because PS deprivation produces an ACh
receptor subsensitivity, as well as a DA
receptor supersensitivity, the evaluation of
yawning behavior in PS deprived animals seemed
adequate to better understand the postulated
relationship between these neurotransmitter
systems. Thus, in the present study, we tested
whether manipulations on these systems would
result in change of PS deprivation induced
inhibition of yawning behavior.
DISCUSSION
Induction of yawning behavior appears to be
dependent on a balance between DAergic and
AChergic systems. This does not seem to be the
case for reversal of yawning inhibition
resulting from PS deprivation. Our results
showed that during the deprivation period only
treatment with an AChergic antagonist was
effective in counteracting PS deprivation
effects on pilocarpine-induced yawning. Atropine
effect was quite specific, because it did not
reverse apomorphine-induced yawning.
Furthermore, neither DAergic agonist nor
antagonist affected PS deprivation induced
inhibition of yawning. This result suggests the
DAergic system involved with this behavior is
different from that involved with stereotypy and
aggressiveness, because pretreatment with
amphetamine and L-dopa reversed PS deprivation
effects on these behaviors.
Yawning is elicited, among several other
manipulations, by activation of postsynaptic ACh
receptors or presynaptic DA receptors,
suggesting a DA-ACh link mediating this
behavior, via DA inhibition and, consequently,
ACh activation. This hypothesis was further
supported by several studies, although it is
still not clear which receptors are responsible
for this behavior. There is a controversy about
the mechanisms by which yawning is elicited.
Several authors suggest yawning is mediated by
stimulation of presynaptic DAergic receptors. On
contrary, Serra et al. propose that this
behavior is elicited by stimulation of a special
population of postsynaptic DA receptors, and D1
and D2 receptors' supersensitivity would inhibit
this special receptor. Thus, studies using
amphetamine pretreatment do not result in
inhibition of yawning induced by low doses of
apomorphine, leading the authors to suggest that
D2 presynaptic receptors are not the mediators
of yawning behavior. In addition to this
hypothesis, behavioral data suggest yawning as a
D3-dependent phenomenon. Results from
biochemical and molecular cloning techniques
support the idea of DA receptor subtypes other
than the classical D1 and D2 receptors
described.
Inhibition of pilocarpine-, physostigmine-,
and apomorphine-induced yawning is observed
following PS deprivation. This manipulation is
believed to inhibit DAergic transmission,
leading to increased AChergic transmission.
Supposedly, the systems respond to PS
deprivation with a presynaptic DA and a
postsynaptic ACh receptor subsensitivity.
Cholinergic system appears to have an important
role in mediating PS: M2 ACh receptor agonists
trigger this sleep stage. Moreover, an
autoradiographic study in 96-h PS deprived
animals reveals a M2 ACh receptor
downregulation, suggesting increased ACh
transmission during PS deprivation. Thus,
atropine treatment during deprivation could
antagonize the suggested subsensitivity of
AChergic receptors induced by PS deprivation.
Recently, Szymusiak et al. reported reversal of
atropine-induced PS inhibition at high
(30°C) ambient temperature. Supposedly,
both high temperature and PS deprivation, induce
an increase in ACh neurotransmission.
Low doses of haloperidol block presynaptic
DA receptors, and this effect should prevent DA
receptor subsensitivity induced by PS
deprivation. The lack of haloperidol effect,
observed in this study, could be a consequence
of treatment schedule; it is possible that daily
injections during 4 days was not long enough to
alter receptor sensitivity. Tufik, however,
observed changes in receptor sensitivity
following acute treatment with haloperidol.
Similarly, Greenshaw et al. referred to several
studies demonstrating short-term
neuroleptic-induced increase in DA receptor
binding. In addition, the hypothesis that
normalization of dopaminergic supersensitivity
as a result of methamphetamine treatment during
PS deprivation would restore the frequency of
yawns was not corroborated by our findings.
Therefore, these data reveal that classical
manipulations of dopaminergic system, such as
methamphetamine and haloperidol treatments, had
no effect on yawning frequency of PS deprived
rats. DA system appears to be affected sooner by
PS deprivation, and to recover later than the
ACh system, suggesting that PS
deprivation-induced changes on these systems
occur at different moments. It is possible that
reversal of yawning inhibition induced by PS
deprivation also occurs sooner for AChergic than
DAergic system. Our results support this
hypothesis and also suggest an independent
mediation of both systems on reversal of PS
deprivation-induced yawning inhibition.
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