The neuropharmacology of yawning
Argiolas A, Melis MR
A trial of subcutaneously injected apomorphine for parkinsonian off-state events
Dewey RB
Drugs affecting dopamine neurons ans yawning behavior
Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior
Collins G et al









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mise à jour du 14 février 2002
 Brain Research
1987; 415; 98-104
Apomorphine-induced penile erection and yawning: site of action in brain
Maria Rosaria Melis, Antonio Argiolas and Gian Luigi Gessa
Institute of Pharmacology, University of Cagliari, Cagliari (Italy)
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren
Introduction : The systemic administration of low doses of dopamine (DA) agonists, such as apomorphine, piribedil, lisuride and 3-PPP, induces yawning and penile erection in rats. Such a response is apparently mediated by the stimulation of central DA receptors of the D2 type, according to the nomenclature of Kebabian and Calnell. Indeed, both penile erection and yawning are induced by D2 DA agonists, but not by selective Dl DA agonists such as SKF 38393, and are prevented by selective D2 DA antagonists such as sulpiride . Unlike low doses, high doses of D2 DA agonists induce hypermotility and stereotypy, but suppress penile erection and yawning. Experimental evidence has shown that hypermotility and stereotypy by high doses of D2 DA agonists are due to the stimulation of postsynaptic DA receptors localized in the caudate nucleus and in the nucleus accumbens.

On the contrary, the localization of DA receptors mediating yawning and penile erection is still controversial. It has been suggested that yawning induced by DA agonists is mediated by DA 'autoreceptors', a special kind of DA receptors located on the nerve endings and cell bodies of the dopaminergic neuron itself, whose stimulation leads to the inhibition of neuronal dopaminergic activity. Such an hypothesis is supported by studies showing that yawning is abolished by the destruction of the nigrostriatal DA system by 6-hydroxydopamine (6OHDA). However, the above conclusions have been questioned by recent experimental evidence suggesting that DA receptors mediating yawning are postsynaptic DA receptors . As to the DA receptors mediating penile erection, the problem is even more complicated, since it has still to be determined whether or not these DA receptors are the saine that mediate yawning or another population of DA receptors. In order to clarify the above controversy, it would be helpful to determine the brain area where DA agonists act to induce pende erection and yawning. In an attempt to identify such brain area(s), we have microinjected apomorphine into discrete brain areas through chronically implanted guide cannulae. The results show that low doses of apomorphine and other DA agonists induce penile erection and yawning when injected into the paraventricular nucleus of the hypothalamus (PVN).


Discussion : The present results show that nanogram amounts of apomorphine induce penile erection and yawing when injected into the hypothalamic PVN. Although spreading of the drug to hypothalamic areas surrounding the PVN is possible, it is unlikely that such responses are mediated by other hypothalamic nuclei since injection of apomorphine in regions very close to the PVN, such as the ventromedial and dorsomedial nucleus and the preoptic area, was ineffective. Similarly, ineffective were also injections into the substantia nigra, the striaturn and nucleus accumbens, the brain areas that contain the highest levels of DA and that mediate hypermotility and stereotypy induced by DA agonists. The ineffectiveness of an apomorphine injection into the striatum to elicit yawning is in contrast with previous studies showing that yawning is induced by the bilateral injection of apomorphine into the caudate nucleus. The discrepancy may be explained by the fact that in these studies doses of apomorphine (5µg and higher) were used that were too high. Such doses have probably resulted in a spread of the drug to the active site. The present results are also in contrast with the finding that the destruction of the nigrostriatal DA system by 6-OHDA abolishes yawning induced by apomorphine. A possible explanation for the failure of apomorphine to induce yawning might be the development of DA receptor supersensitivity, that favors the appearance of hypermotility and stereotypy masking yawning and pende erection. Alternatively, il might be that an intact nigrostriatal DA systern is necessary for the expression of yawning.

As to the possible site of action of apomorphine in the PVN, il is noteworthy that D2 DA receptors have been detected in this area, and that the PVN contains the cell bodies of DA neurons of the A14 group, that constitute, the so-called incertohypothalamic DA system, together with those of the Al l and A13 groups. This system consists of short, locally projecting neurons whose fibers arborize extensively soon after they have left their cell bodies and also project to the anterior and lateral hypothalamus and preoptic area . Recent experiments suggest the presence of DA autoreceptors on the incertohypothalamic DA neurons controlling DA synthesis. Therefore, penile erection and yawning might be due to the autoreceptor-mediated inhibition of such neurons. However, the finding that penile erection and yawning were el cited by (+)-3-PPP, but not by (-)-3-PPP, and that apomorphine responses were antagonized by SCH 23390 supports the hypothesis that yawning reflects activation of postsynaptic DA receptors rather than autoreceptor-mediated inhibition of DA transmission. In fact, as previously discussed for yawning induced by systemically injected apomorphine, both 3-PPP enantiomers are DA autoreceptor agonists, but have different postsynaptic properties: namely, al this site the (+)-enantiomer is an agonist while the (-)-enantiorner is an antagonist. (-)-3-PPP, because of its pre- and postsynaptic action, would have been more active than the (+)-enantiomer, if yawning reflected the inhibition of DA transmission. Similarly, SCH 23390 has been shown to antagonize postsynaptic DA receptor-mediated effects of apomorphine, but to be unable to antagonize DA autoreceptor-mediated responses: SCH 23390 would have been ineffective in antagonizing the apomorphine response, if DA autoreceptors in the PVN behaved as DA autoreceptors in the nigrostriatal DA system.

Irrespective of their location, DA receptors mediating yawning and penile erection apparently are of the D2 type because of their response being reproduced by the selective D2 agonist LY 171555, but not by the Dl agonist SKF 38393, and antagonized by sulpiride, a specific D2 antagonist. However, the finding that SCH 23390 antagonized apomorphine-induced yawning and penile erection is in agreement with recent observations showing that this rather selective Dl antagonist paradoxically abolishes other responses to apomorphine, which are considered to be mediated by D2 receptors. These responses also include yawning induced by systemic apomorphine or LY 171555 administration 13 . An explanation for this paradox might be sought in the still unknown relationship between D1 and D2 receptors.

The present results suggest that the hypothalamic PVN is the target of systemically injected DA agonists to produce yawning and pende erection, and that the incertohypothalamic DA system has a physiological role in controlling these behaviors. Il is noteworthy that: (a) stretching-yawning syndrome and penile erection can be induced, other than by DA agonists, by ACTH-derived peptides and by oxytocin, (b) that the hypothalamic regions surrounding the third ventricle are the most sensitive brain areas for the induction of these effects by ACTH, (c) that the PVN, where oxytocinergic neurons are located, is the most sensitive site in the brain for oxytocin-induced penile erection and yawning. The link between DA, oxytocin and ACTH in controlling yawning and/or pende erection and the link between penile erection and yawning are still obscure.

Pharmacological interactions suggest that DA, oxytocin and ACTH receptors controlling the above responses are situated downhill one after the other in a sequence. Accordingly, blockade of DA receptors by neuroleptics fails to inhibit the effect of oxytocin and ACTH whereas blockade of oxytocin receptors with the potent oxytocin antagonist, d(CH2)5 Tyr(Me)-Orn-vasotocin, results in the inactivation of apomorphine and oxytocin but not ACTH responses. Finally, DA agonist-induced yawning, like ACTH-and oxytocin-induced yawning and penile erection, is abolished by pretreatment with antimuscarinic drugs. Since yawning also is induced by the systemic injection of muscarinic agonists it has been suggested that yawning is a consequence of an increased cholinergic transmission secondary to the inhibition of DA release. However, this hypothesis has not been proved yet by injecting directly antimuscarinic drugs into discrete brain areas. Hence the site where antimuscarinic agents act to abolish yawning is still unknown. As to a possible interaction between DA and acetylcholine in the PVN, cholinergic fibers and terminals as well as muscarinic receptors have been identified in this nucleus. However, it is still unknown if a direct interaction exists between the two neurotransmitters.

In conclusion, the present results indicate for the first time that the incertohypothalamic DA neurons play an important physiological role in controlling yawning and pende erection.