mise à jour du
1 septembre 2003
Br J Pharmacol
Interactions of drugs acting on central dopamine receptors and cholinoceptors on yawning responses in the rat induced by apomorphine, bromocriptine or physostigmine
Zarrindast MR, Poursoltan M
Department of pharmacology, Medical faculty, Teheran, Iran
Index de tous les travaux de MR Zarrindast


Introduction : Biochemical and pharmacological evidence indicate that two différent dopamine receptors, termed D1 and D2 mediate the dopamine functions in brain. These two categories of dopamine receptors are distinct molecular entities with différent distributions. Both D1 and D2 dopamine receptors, which exist in striatum, can stimulate and inhibit the striatal cyclic AMP formation respectively.
Striatum contains the highest concentration of acetylcholine in the brain . Available evidence suggests that dopamine receptors have a regulatory role on striatal acetylcholine. The opposing effects of D1 and D2 receptors on striatal cholinergic neurones have also been shown.
Yawning can be induced in experimental animals by the dopamine receptor agonists apomorphine, norpropylnorapomorphine and lisuride. It bas been proposed that stimulation of dopamine autoreceptors, and therefore inhibition of dopaminergic transmission in, the brain, causes yawning. This behaviour appears to be centrally mediated and due to septal and striatal D2 receptor activation, although results obtained by some workers (Morelli et al., 1986) contradict the hypothesis that apomorphine produces yawning by acting on dopamine autoreceptors.
Some investigators have suggested that central cholinergic mechanisms arc involved in yawning behaviour. Drugs acting on both cholinoceptors and dopamine receptors have been used to investigate the influence of D1 and D2 receptors on yawning behaviour.[...]
Discussion :
Apomorphine with D1 and D2 agonist properties in small doses (0.1-0.6mgkg) induced yawning in rats. This syndrome was decreased by increasing the dose of the drug. Pretreatment of animals with sulpiride a D2 dopamine receptor antagonist reduced the ability of apomorphine to induce yawning. Our present results are in agreement with previous observations of others that apomorphine influences yawning biphasically in rats.
Such a biphasic effect bas been attributed to the successive involvement of D1 and D2 dopamine receptors; the lower doses of apomorphine stimulate D2 receptors which decrease tonic dopaminergic transmission with a consequent . induction of yawning, while the higher doses activate D1 receptors and cause the abolition of yawning .
Pretreatment of animals with low doses of the specific D1 receptor antagonist SCH 23390 increased the ability of apomorphine to induce yawning. When dopamine activation of D1 sites is impaired by SCH 23390, apomorphine activates only D2 sites and therefore more frequent yawning can be observed. Administration of SCH 23390 alone also induced a low degree of yawning in rats, which may indicate inhibition of D1 and unmasking of D2 agonist properties of endogenous brain dopamine.
These effects of SCH 23390 confirm the hypothesis that D1 receptor stimulation can decrease the yawning episodes and contradict the suggestion of some investigators that autoreceptors are not involved, e.g. Morelli et al. (1986), who found SCH 23390 was able to antagonize yawning induced by apomorphine. For further evaluation of the opposite influences of D1 and D2 dopamine receptor activation on yawning, some studies were carried out with D1 and D2 agonists. Bromocriptine, a D2-agonist bas been reported to induce yawning through the stimulation of dopamine D2-receptors in the rat striatum and septum. In the present study, bromocriptine caused yawning dosedependently. The effect was decreased in animals pretreated with sulpiride. SCH 23390 did not alter the frequency of yawns induced by bromocriptine. These findings support the view that D2-receptor stimulation may cause yawning.
SKF 38393 which does not induce yawning is a D1 receptor agonist devoid of D2 receptor stimulation properties . This drug decreased yawning induced by both apomorphine and bromocriptine. These data may suggest that D1 receptor stimulation exerts opposite influence on yawning. On the other band, the ability of SKF 38393 to stimulate dopamine-sensitive adenylate cyclase has been shown. It has been suggested that activation of D1 receptors is associated with stimulation of adenylate cyclase while D2 receptor activation may cause inhibition of cyclic AMP formation in striatum. Theophylline which increases cycflc AMP levels, inhibits yawning induced by apomorphine, bromocriptine or physostigmine. Whether the opposite effects of D1 and D2 receptors on yawning behaviour are due to an increase or decrease of cyclic AMP levels is not clear and remains to be elucidated.
Previous investigations have pointed out the involvement of the cholinergic system in the induction of yawning syndrome. The present data show that neostigmine, which is not able to enter the CNS, does not induce yawning behaviour and that atropine can antagonize episodes of yawning in rats treated with apomorphine, bromocriptine or physostiginine. This points to a possible central muscarinic component in the yawning induced by these drugs. These results are supported by the suggestion of Yamada & Furukawa (1980) who showed that apomorphine induced yawning through indirect activation of cholinergic neurones. Our results show that bromocriptine potentiates and SK&F 38393 decreases the frequency of yawns induced by physostigmine. li is therefore postulated that yawning may be induced through a cholinergic activation mechanism, while D1 and D2 receptor stimulation may have opposite effects on this behaviour.
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-Zarrindast, MR, Jamshidzadeh A Inhibitory effect of morphine on yawning induced by cholinoceptor and dopamine D2 receptor activation in rats Br J Pharmacol 1992; 105; 3; 675-8
-Zarrindast MR, Toloui V, Hashemi B Effects of GABAergic drugs on physostigmine-induced yawning in rats; Psychopharmacology (Berl) 1995; 122; ; :297-300
-Zarrindast MR, Fazli-Tabai S, Semnanian S, Fathollahi Y Influence of different adrenoceptor agonists and antagonists on physostigmine-induced yawning in rats. Pharmacol Biochem Behav 1999; 62; 1; 1-5