mise à jour du
27 février 2003
Eur J Pharrnacol
1987; 140; 215-219  
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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-Tufik S Does REM sleep deprivation induce subsensitivity of presynaptic dopamine or postsynaptic acetylcholine receptors in the rat brain? European Journal of Pharrnacology 1987; 140; 215-219