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mise à jour du 10 juillet 2003
Psychopharmacology
1987; 91; 330-337
lexique
Yawning is elicited by D2 dopamine agonists but is blocked by D1 antagonist
Serra G., Collu M. and Gessa GL.
Institute of Pharmacology, University of Cagliari, Italy
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The administration of sinall doses of apomorphine and other dopamine (DA) receptor agonists produces repeated episodes of yawning in rats (Mogilnicka and Klimek 1977; Baggio and Ferrari 1983; Protais et al. 1983; Serra et al. 1983a, b, 1984a, b, 1986a; Stahle and Ungerstedt 1984) and in humans (Corsini et al. 1977).

This behavioural response scems to be due to the stimulation of CNS DA receptors, being prevented by centrally acting neuroleptics (Mogilnicka and Klimek 1977; Nickolson and Berendsen 1980; Dubec et al. 1982; Gower et al. 1984; Stahle and Ungerstedt 1984; Serra et al. 1986a) but not by domperidone (Gower et al. 1984; Stahle and Ungerstedt 1984, Serra et al. 1986 a), a DA receptor blocker which does not cross the blood-brain barrier (Laduron and Leysen 1979).

It has been suggested that DA receptors mediating yawning might be identified with DA autoreceptors, the stimulation of which results in the inhibition of DA synthesis and release and of dopaminergic firing (see Di Chiara et al. 1978). Consequently, yawning has been considered a behavioural correlate of the inhibition of DA transmission. However, this hypothesis is mainly based on the fact that the doses of DA receptor agonists needed to produce yawning are within the same minute doses needed to stimulate DA autoreceptors, while higher doses, which stimulate both auto- and postsynaptic DA receptors, produce locomotor hyperactivity and stereotypy and suppress yawning (Mogilnicka and Klimek 1977; Baggio and Ferrari 1983; Protais et al. 1983; Stahle and Ungerstedt 1984; Gower et al. 1984).

We have, however, recently provided evidence suggesting that DA receptors mediating yawning belong to a special population of central DA receptors which are sensitive to DA agonists as DA autoreceptors, but which are located postsynaptically (Serra et al. 1986a).

The aim of the present study was to clarify whether DA receptors mediating yawning were of D1 (positively linked to adenylate cyclase) (see Stoof and Kebabian 1981) or D2 type (not linked or negatively linked to adenylate cyclase) (see Stoof and Kebabian 1981; Onali et al. 1984). Therefore, we compared the ability of apomorphine, a mixed D1-D2 agonist (Kebabian and Calne 1979), LY 171555, a selective D2 agonist (Stoof and Kebabian 1984; Plantjé et al. 1985), and SKF 38393, a selective D1 agonist (Stoof and Kebabian 1981), to induce yawning in rats. We also studied the effect of sulpiride, a selective D2 antagonist (Spano et al. 1979), and SCH 23390, a selective D1 antagonist (Hyttel 1983), on the yawning response to apomorphine and LY 171555. [...]

 
Wa have confirmed that apomorphine, a mixed D1-D2 receptor agonist, induces yawning, while the selective D1 agonist, SKF 38393, is inactive. Morever, we have shown that LY 17155, a selective D2 agonist, also induces yawning. These results suggest that DA agonist are of the D2 type. In accordance with this hypothesis, we found that yaning response to either apomorphine or LY 171555 was antaginized by very small doses of the selective D2 antagonist, (-) sulpiride. Thus, it was surprising to find that minute doses of the selective D1 antagonist SCH 23390 prevented both apomorphine- and LY 171555-induced yawning.

One possible explanation for this paradox is that SCH 23390, in spite of its in vitro specifity for D1receptors, might also block in vivo D2 receptors. This possibility is unlikely, however, since there is convincing evidence that, within the dose range used in the present work, SCH 23390 also selectively blocked the D1receptors subtype in vivo (Stoof and Kebabian 1984). Indeed, SCH 23390 has a low antiemetic and hyperprolactinemic potency, as well as a poor ability to antagonize dopaminergic inhibition of syrnpathetic outflow, all considered pure D2 effects. Chronic treatment with SCH 23390 at the dose range used in the present experiments produces a selective increase in the number of striatal D1receptors, and fails to modify D2 receptors (Porceddu et al. 1985). Doses of SCH 23390 up to 1 mg/kg fail to block DA autoreceptors (Mereu et al. 1985; Gessa et al. 1986), a special population of D2 receptors (Lehmann et al. 1983; Pinnock 1983; Walters et al. 1986).

The antagonism of SCH 23390 to the yawning response cannot be explained by its action on any known non-dopaminergic system. Thus, SCH 23390 has very little affinity for different non-dopaminergic receptors such as those for noradrenaline, histamine, acetylcholine and benzodiazepines (Hyttel 1983; Cross et al. 1983; Cristensen et al. 1984). At the doses which antagonize yawning, SCH 23390 has no effect on the classical serotoninergic behavioural syndrome induced by the 5-HT agonists (Pugh et al. 1985). The latter observation is in agreement with the modest affinity of SCH 23390 for 5-HT receptors (Hyttel 1983; Cross et al. 1983) and also suggests that, while low doses of SCH 23390 antagonize the yawning response, they do not cause a general sedative effect depressing behaviour.

It has recently been reported that stereotypy and stimulation of motor activity induced by the administration of apomorphine or other DA agonists, which are considered D2 mediated phenomena, are also potently antagonized by SCH 23390 (Christensen et al. 1984; Mailman et al. 1984; Molloy and Waddington 1984; Gessa et al. 1985; Pugh et al. 1985). These observations have led the above authors to propose the existence of a functional link between some populations of D1and D2 receptors, so that blockade of the former produces a functional inactivation of the latter (Christensen et al. 1984; Gessa et al. 1985; Molloy and Waddington 1984; Pugh et al. 1985). According to Pugh et al. (l 985), such a functional link might operate in the same synaptic membrane in such a way that the blockade of D1receptors alters the affinity of D2 receptors for the agonists. Alternatively, SCH 23390 might block D1receptors in a dopaminergic system which exert a modulatory influence on those processes which are initiated by D2 stimulation. These considerations suggests that the blockade of yawning by SCH 23390, induced by selective stimulation of D2 receptors, might be explained assuming that, like D2 receptors mediating motor activity and stereotypy, D2 receptors mediating yawning are also fonctionally interconnected with D1receptors.

The finding that SCH 23390 antagonizes DA agonist induced yawning provides indirect support to our hypothesis that DA receptors mediating yawning are distinct from DA autoreceptors (Serra et al. 1986a). In fact, SCH 23390 is unique among neuroleptics in that it fails to block DA autoreceptors (Mereu et al. 1985; Carlson et al. 1986; Gessa et al. 1986).

In conclusion, our results suggest that DA receptors mediating yawning are a population of postsynaptic DA receptors of the D2 type which are as sensitive to DA agonists as DA autoreceptors. Like DA receptors, which mediate the classical excitatory responses of motor activity and stereotypy induced by DA agonists, D2 receptors mediating yawning appear to be functionally linked to D1 receptors.

These findings further support our hypothesis that yawning is a behavioural correlate of increased DA transmission and might be considered a first degree of arousal, mediated by activation of a most sensitive population of postsynaptic DA receptors (Serra et al. 1984b, 1986a, b). Further activation of DA transmission might progress to higher level of arousal, locomotor activity and stereotypy. This interpretation is consistent with several observations which suggest that yawning may be considered a behavioural response subserving arousal (see Serra et al. 1986b).

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