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3 juin 2004
Europ J Pharmacology
1986; 120; 187-192
Dopamine receptors médiating yawning
are they autoreceptors
Serra G, Collu M, Gessa GL
Department of Neuroscience, University of Cagliari, Cagliari, Italy


Small doses of apomorphine and other dopamine (DA) receptor agonists produce repeated episodes of yawning in rats and in humans. This behavioural response seems to be due to the stimulation of DA receptors in the central netvous system (CNS) being prevented by centrally acting neurolepticsbut not by domperidone, a DA receptor blocker which does not cross the bloodbrain barrier.
It has been suggested that DA receptors mediating yawning have to be identified with DA autoreceptors. DA autoreceptors are a special kind of DA receptors located on the dopaminergic neuron itself, the stimulation of which results in inhibition of dopaminergic firing and of DA synthesis and release.
This hypothesis is mainly based on the observation that the minute doses of DA receptor agonists needed to produce yawning are within the same range as those needed to stimulate DA autoreceptors, while the higher doses, which stimulate postsynaptic DA receptors as well, produce locomotor hyperactivity and stereotypy and suppress yawning. The presynaptic origin of the yawning response to DA agonists is further suggested by the fact that it is abolished by bilateral 6-OH-dopamine (6-OH-DA)-induced denervation of the striatum and olfactory tubercles and by the fact that yawning is elicited by DA agonists such as 3-(3-hydroxyphenyl)-N-n-propylpiperdine (3PPP) and TL-99, which are considered to preferentially, or selectively stimulate DA autoreceptors.
On the basis of these observations it has been proposed by various authors, including ourselves that yawning is a behavioural consequence of DA autoreceptor mediated inhibition of DA-transmission. In addition, since anticholinergic drugs antagonize apomorphine-induced yawning, Yamada and Furukawa (1980) have suggested that this behaviour is mediated by cholinergic activation secondary to the inhibition of DA transmission.
However some data argue against this hypothesis. For example, inhibition of DA transmission obtained by other means e.g. neuroleptic administration or-degeneration of DA neurons is not associated with yawning. Moreover, the selectivity of 3PPP and TL-99 for DA autoreceptors has been questioned and their stimulating property for postsynaptic DA receptors has been demonstrated. In particular, one of the two enantiomers of 3PPP, (+)-3PPP was found to elicit yawning while the other, (-)-3PPP, was found to be either inactive or less active than the (+)-enantiomer. The two enantiomeric forms differ in their action on auto- and postsynaptic DA receptors. (-)-3PPP activates DA autoreceptors but is an antagonist at postsynaptic DA receptors, whereas ( +)-3PPP is a DA agonist at both autoreceptors and at postsynaptic DA receptors as weil. If yawning reflected the inhibition of DA transmission, (-)-3PPP, because of its pre- and postsynaptic action, should have been more effective than the ( + ) enantiomer.
All these considerations prompted us to reinvestigate the nature and the location of DA receptors mediating yawning. The results suggest that yawning is mediated by the stimulation of a population of DA receptors having a high affinity for DA agonists similar to that of DA autoreceptors but located postsynaptically. [...]
Discussion : We have confirmed that (+)-3PPP induces yawning while its (-)enantiomer is inactive.
Both enantiomers of 3PPP are considered to act onagonists at DA autoreceptors but to have diifferential effects postsynaptically. Namely at high doses (-)-3PPP is an antagonist, while (+)-3PPP is an agonist of postsynaptic DA receptors.
If yawning reflected the inhibition of DA transmission, (-)-3PPP, because of its pre- and post synaptic action, it should have produced the response more effectively than the ( + ) enantiomer. On the contrary only the (+) enantiomer, acts as an agonist for postsynaptic DA receptors was capable of inducing yawning. Further support for the hypothesis that yawning reflects activation of postsynaptic DA receptors rather than inhibition of DA transmission is, paradoxically offered by the results with reserpine, a drug that inhibits DA transmission. In fact, reserpine elicited yawning 24 h after treatment but not at 6 and 12h when DA depletion and impairment of DA transmission are known to be maximal. Moreover, reserpine-induced yawning was antagonized both by the centrally actingDA receptor antagonist, (-)sulpiride, and by the
inhibitor of tyrosine hydroxylase, a-MT, suggestting that DA synthesis and release are needed for the yawning response. An important aspect of these results is that they are the first evidence that yawning may be induced by endogenously released DA.
It is likely that the newly synthetized DA, released in the synaptic cleft, becomes sufficient to induce yawning at 24 h after treatment, partly because super-sensitivity has developed at postsynaptic DAreceptors. This possibility is supported by the finding that the administration of a dose of ( + ) -3PPP ineffective in control rats, was effective in further increasing th number of yawns in reserpine-treated animals. This finding is in agreement with that of Yamaka Furukawa (1980), showing that reserpine potentionates apomorphine-induced yawning, and with that of Arnt et al. (1983b) indicating that 3PPP shows ahigh efficacy in stimulating supersensitive post-synaptic DA-receptors.
In agreement with previous reports we found that (+)-3ppP-induced yawning was antagonised by haloperidol, a blocker of D1 and D2 receptors and by (-)sulpiride, a selective D2 antagonist, butnot by domperidone, a peripheral DA receptor blocker. Moreover, as mentioned above, we found that (-)sulpiride also blocked reserpine-induced yawning.
Finally, unpublished results from our Institute have shown that SCH 23390, a rather selectiveD1 receptor blocker fails to prevent apomorphine-induced yawning. These findings suggest that, irrespective of their location, DA receptors mediating yawning may be classified as D2 receptors, according to the classification of Kebabian and Calne (1979). However, with their higher sensitivity to agonists, these receptors differ markedly from D2 receptors subserving motor stimulation and stereotypies.
As to the physiological meaning of yawning, it should be recalled that this bebaviour, often associated with stretching, is displayed when sleep is pressing because of fatigue or boredom, but sleep has to be postponed because it might be dangerous or, as in civilised society, impolite (socially dangerous). Probably yawning and stretching are an elotutionary vestige of a behaviour subserving arousal when attention is decreasing in front of a danger. This interpretation might explain why this behaviour has peculiar traits in common with behaviour (typically, in a cat, wide opening the mouth, showing of teeth and claws, back and tail and stretching of the legs).
Yawning might be considered to indicate a low of degree arousal, mediated by the activation of t he most sensitive population of DA receptors. Further activation of DA transmission might progress to full arousal, exploratory behaviour, steretyped sniffing, licking and gnawing. This hypothesis offers a logical explanation for the fact that yawning and stereotypy are mutually exclusive, namely when the latter is elicited the former is suppressed.
Accordingly, it is likely that DA agonists fail to induce yawning in 6-OH-DA lesioned animals, a condition in which presynaptic terminals bearing DA autoreceptors are lost, simply because they produce a higher degree of arousal, due to the supersensitivity of postsynaptic DA receptors. Whether the different behaviours elicited by DA agonists reflect different populations of receptors or the recruitment of a larger number of the same kind of receptors is not known.
Finally in addition to DA agonists, ACTH and MSH-related peptides also elicit yawning and are released in response to stress and subserve camouflage purposes, respectively. Another intriguing problem is whether DA receptors are also involved in the yawning response to ACTH and MSH peptides or, vice versa, whether the release of such peptides mediates the yawning induced by DA agonists.
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