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26 février 2006
Pharmacol Biochem Behav
1995; 52; 3; 485-488
Atropine increases pilocarpine-induced yawning
behavior in paradoxical sleep deprived rats
Lobo LL, de Medeiros R, Hipolide DC, Tufik S
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.
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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