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19 janvier 2006
Apomorphine-induced yawning in rats is abolished by
bilateral 6-hydroxydopamine lesions
of the substantia nigra
A.J. Stoessl, C.T. Dourish, S.D. Iversen
Merck Sharp & Dohme Research Lab, Harlow, Essex, UK


Yawning is a physiological response that occurs spontaneously, and is associated with fatigue and recovery from stress. Numerous pharmacological agents induce yawning behaviour in animals, including the peptide hormones ACTH, a-MSH, prolactin and oxytocin. The cholinergic agents physostigmine and pilocarpine induce yawning in association with chewing mouth movements, and this is inhibited by muscarinic but not nicotinic blockade. Finally, numerous investigators have demonstrated yawning and sexual arousal in response to apomorphine and other dopamine agonists, at doses presumed to be selective for presynaptic autoreceptors. Dopamine agonist-induced yawning is inhibited by selective D2 antagonists but may be either attenuated or potentiated by presynaptic dopamine depletion with reserpine. It has thus been proposed that yawning results from disinhibition of striatal cholinergic activity which is under tonic dopaminergic inhibition, mediated by selective activation of autoreceptors located on nigral dopamine cells or their striatal terminals.
Previous work provided further support for the hypothesis that nigrostriatal dopaminergic autoreceptors are necessary for the behaviour induced by low doses of apomorphine. It was found that chemical denervation with intrastriatal 6-hydroxydopamine (6-OHDA) abolished the yawning-penile erection syndrome in rats. Two potential problems with that study required further delineation, however. First, it is conceivable that the relatively high dose of 6-hydroxydopamine employed (16 µg) could exert non-selective toxicity, thereby affecting post-synaptic striatal receptors. SeconD1y, only a single dose of apomorphine (100 µg/kg SC) was used. Since the dose response curve for apomorphine-induced yawning is bell-shaped, a marked shift of this curve to the left could explain the failure of apomorphine to induce yawning in chemically-lesioned animals.
In the present study, we have addressed these issues by producing cell body lesions of the substantia nigra using 6-OHDA, and by examining the effects of a range of doses of apomorphine.
These results clearly indicate that apomorphine-induced yawning is dependent on intact nigrostriatal dopamine projections. Although some yawning following apomorphine was seen in the lesioned animals, this was greatly attenuated when compared to controls. Preservation of a partial response is not surprising, since the biochemical data indicate only moderate depletion of striatal dopamine, suggesting that the lesions were incomplete. The most logical explanation for these findings is mediation of the behavioural syndrome by the action of apomorphine on dopamine autoreceptors located on presynaptic nigrostriatal terminals and! or nigral cell bodies. Autoreceptor activation would result in suppression of tonic activity in the dopamine neurons and secondary disinhibition of striatal cholinergic interneurons. Mediation of yawning by dopamine terminal autoreceptors seems likely, as yawning is also abolished by striatal 6-OHDA lesions and is induced by injections of dopamine agonists into striatum and nucleus accumbens but not by injections of these drugs into substantia nigra or ventral tegmental area. Administration of dopamine agonists into the accumbens is much less effective in eliciting yawning than are striatal infusions. This may explain the blockade of yawning in our animals, despite intact dopamine projections to the accumbens.
It has been argued that the yawning response is mediated by a special class of high-affinity post-synaptic dopamine receptors. Attenuation of the response in chemically denervated animals could then be explained by post-synaptic dopamine receptor supersensitivity and induction of stereotypy in these animals by low (i.e. putative "autoreceptor") doses of apomorphine. The present data show that this is unlikely to be the case, however, for two reasons. First, the yawning dose response curve was not shifted to the left in the lesioned animals, but simply lowered in amplitude. SeconD1y, there were no significant increases in stereotyped sniffing and chewing behaviour in the lesioned animals.
Other investigators have examined the effects of dopamine depletion on agonist-induced yawning, using reserpine and/or a-methyl-para-tyrosine. M ogilnicka and Klimek (1977) reported that both drugs attenuated the yawning induced by a single dose (50 µ/kg SC) of apomorphine, while Yamada and Furukawa (1980) observed increased yawning following 250 µg/kg IP. Morelli et al. (1986) found that 16-h pretreatment with reserpine shifted the apomorphine-induced yawning dose response curve to the left, but the same group have recently shown that 6-h pretreatment with reserpine (sufficient to result in 95% dopamine depletion) shifts the yawning dose response curve for other dopamine agonists (BHT 920, LY 171555 & (+)-3-PPP) to the right. The effects of reserpine on autoreceptor-mediated responses are uncertain at this time. Clearly, reserpine treatment cannot be considered equivalent to chemical denervation with 6-OHDA. This is particularly well demonstrated by the induction of spontaneous yawning in rats receiving reserpine 24 h earlier, a response not seen in our 6-OHDA denervated animals.
Although it is attractive to postulate that these findings provide further support for the view that yawning is elicited by auto receptor-mediated inhibition of tonic dopaminergic cell firing and secondary release of striatal cholinergic activity, a number of observations are not adequately explained by this hypothesis, and require further comment. First, although racemic and (+)-3-PPP induce yawning, the (-)enantiomer, which is a selective agonist at autoreceptors, and a postsynaptic D2 antagonist , does not. Although such an agent should clearly result in marked disinhibition of striatal cholinergic neurons, its in vivo effects are complex. Thus, (- )-3-PPP stimulates contralateral circling in animals with unilateral 6-OHDA lesions, an action characteristic of post-synaptic dopamine agonist activity, but increases striatal dopamine synthesis and turnover, suggesting antagonist activity. Furthermore, (-)-3-PPP-induced suppression of locomotor activity is insensitive to D2 blockade, and the (-)-enantiomer, but not (+)-3-PPP, is a weak serotonin antagonist and this may also influence yawning behaviour.
One other difficulty with the hypothesis that apomorphine-induced yawning is presynaptically mediated is the demonstration that it can be blocked by treatment with the selective D1 antagonist SCH-23390, as well as D2 antagonists. It has been argued that this is evidence against the pre-synaptic mediation of yawning, as D1 receptors have generally been thought to be located post-synaptically. The selective D1 agonist SKF-38393 does not induce yawning. Hoever, SCH-23390 does increase the firing rate of nigral dopamine neurons, although it fails to attenuate apomorphine-induced inhibition of nigral cell firing and recent autoradiographic evidence suggests that SCH-23390 may in fact bind to nigral dopaminergic neurons. Furthermore, SCH-23390 was ineffective in further decreasing dopamine agonist-induced yawning in reserpinized animals, and yet attenuated the yawning induced by B-HT 920 (a selective dopamine autoreceptor agonist in non-denervated animals; even in animals with kainate lesions of the striatum. These findings suggest to us that D1 and D2 receptors may be coupled presynaptically as well as postsynaptically, as has been previously suggested by others.
Finally, the relationship between the role of dopamine autoreceptors and peptide hormones in the induction of yawning is far from clear. Laping and Ramirez (1986a) have recently demonstrated that prolactin induces yawning, and have furthermore shown that this is abolished (as is that induced by apomorphine) by 6-OHDA lesions of the nigrostniatal tract. This suggests that prolactin may have an inhibitory effect on the dopaminergic neurons, similar to that resulting from stimulation of autoreceptors. Melis and colleagues (1986) have reported induction of yawning by oxytocin and have localized this response to the paraventricular nucleus of the hypothalamus. Furthermore, they have found that apomorphine is also extremely potent when microinjected into this region. On the basis of other work, they suggest that hypothalamic oxytocin neurons lie downstream to dopaminergic terminals in the response, since apomorphine-induced yawning was blocked by pretreatment with an oxytocin antagonist. Stimulation of oxytocin mechanisms may elicit yawning by an action on ACTH , a peptide which has been known for many years to produce yawning. While dopamine-oxytocin interactions in the hypothalamus may indeed be one potential means for expression of the yawning response, they do not explain its clear reliance on an intact nigrostriatal dopamine system, as demonstrated in this paper and previously, unless one postulates that the nigrostriatal lesions abolish the response by non-specific effects on motor activity. This would appear to be unlikely, in view of the induction of spontaneous yawning by a dose of reserpine (5 mg/ kg) sufficient to produce catalepsy. One can only speculate that yawning may either result from activation of a number of independent brain mechanisms, or that there is some final common pathway which is recruited by many converging routes, perhaps culminating in hippocampal spreading depression.
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