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14 août 2003
Yawning elicited by sytemic and intrastriatal injection of piribedil and apomorphine in the rat
CT Dourish, SJ, Cooper, SR Philips
Psychiatric research division, Saskatchewan health, Canada
Neural basis of drug induced yawning
Cooper SJ, Dourish CT in Neurobiology of Stereotyped Behaviour


Studies on yawning and associated phenomena date back on the observation of Ferrari (1958) that intracisternal administration of the peptide hormones adrenocorticotrophic ormone (ACTH) and melanocyte stimulating hormone a-MSH produce a stretching-yawning crisis in dogs, cats, rabbits, and rats. Recent pharmacological research has focussed on a syndrome elicited by various compounds in rats which consists of yawning, often accompanied by stretching and sexuaI arousal.

We are interested in the proposal that dopamine neurones are involved in the mediation of' yawning and associated responses. Thus, low doses of the dopamine agonists piribedil, apomorphine, nomifensine, lisuride, bromocriptine, lergotrile, and L-dopa, administered systemically, produce yawning, stretching, and penile grooming in rats. At higher doses of the dopamine agonists the yawning disappears and recurrent sniffing is observed. This biphasic effect of dopamine agonists on yawning can be differentially modified by neuroleptic pretreatment. Low doses of neuroleptics antagonise yawning produced by 0.1 mg/kg apomorphine, whereas increasing doses of haloperidol, chlorpromazine, mezilamine, metocloprarnide, and thioridazine make yawning reappear in rats injected with 0.6 mg/kg apomorphine.

There appears to be a relationship between dopamine agonist-induced and peptide-induced yawning. Thus, inhibition of protein synthesis by administration of cycloheximide prevents apomorphine-induced yawning and penile grooming. Similarly, the lack of pituitary peptides caused by hypophysectomy abolishes yawning and penile erection induced by apomorphine.

Additional evidence suggests that cholinergic mechanisms may be involved in the expression of yawning. UrbaHolmgren et al. (1977) have reported that systemic injection of the muscarinic agonists pilocarpine and physostigmine elicits yawning and stretching in infant and adult rats. The elicited responses can be inhibited by pretreatment with the muscarinic antagonist scopolamine. It has been proposed that dopaminergic and cholinergic influences may interact to produce yawning behaviour (Holmgren and Urba-Holmgren 1980). Thus, in cross-blocking studies. it has been demonstrated that scopolamine abolishes apomorphine-induced yawning whereas the neuroleptics spiroperidol and fluphenazine potentiate physostigmineinduced yawning.

There has been no attempt made, to date, to investigate the neural substrates of yawning and associated responses by intracranial application of drugs. The aims of the present study were threefold: first, to describe the effects of microinjection of dopamine agonists into a dopamine-rich terminal region of the forebrain on yawning and associated phenomena and on locomotor activity; second, to compare these effects with those elicited by systemic dopamine agonist administration; and third, to attempt to reverse the elicited behavioural effects by systemic injection of haloperidol and scopolamine. [...]


Local bilateral application of piribedil and apomorphine to the striatum of male rats produced yawning which was both preceded and succeeded by chewing mouth movements. On some occasions, yawning was accompanied by sexual arousal (penile grooming, erection and ejaculation) and forelimb stretching. Both piribedil and apomorphine are direct dopamine receptor agonists, and it therefore seems likely that yawning was produced by dopamine receptor stimulation.

The yawning syndrome produced by central application of piribedil and apomorphine was compared with that elicited by systemic administration of small doses of the same drugs. Both routes of injection produced doserelated yawning and chewing with intermittent penile grooming and stretching. These results confirm that yawnmg is produced by systemic administration of low doses of dopamine agonists (Mogilnicka and Klimek 1977; Protais et al. 1983). In the present study, peak effects on yawning were produced by SC doses of 0.1 mg/kg apomorphine and 2.5 mg/kg piribedil, which is consistent with previous studies on the dose-response effects of dopamine agonists on yawning. In addition, our results indicate that the response involves brain dopamine receptors since yawning is produced by intracerebral application of piribedil and apomorphine. Generally, the syndrome induced by intrastriatal piribedil had a shorter latency to onset and a longer duration than that produced by systemic injection of the drug, which suggests that the response is centrally mediated. Indeed, it seems implausible that the response could be due to stimulation of peripheral dopamine receptors, since it has recently been reported that the peripheral dopamine antagonist domperidone does not inhibit yawning induced by systemic apomorphine. In contrast, central dopamine receptor blockade by haloperidol abolishes yawning induced by systemic or intracerebral dopamine agonists.

Interestingly, only one previous study has noted that yawning elicited by SC piribedil is associated with increased chewing mouth movements. The present data convincingly demonstrate that there is a sigificant correlation between yawning and chewmg produced by both systemic and intracranial administration of dopamine agonists. Therefore, we believe that chewing is an integral part of the yawning response in rats. Furthermore, haloperidol pretreatment or bilateral 6-hydroxydopamine (6-OHDA) lesions of the striatum abolish yawning and chewing induced by dopamine agonists.

Yawning induced by systemic dopamine agonist injection is thought to be the consequence of an inhibition of dopaminergic transmission mediated by the stimulation of dopamine autoreceptors in the brain. Thus, doses of dopamine agonists which induce yawning after systemic injection are within the range thought to activate autoreceptors, but lower than doses required to produce signs of postsynaptic dopamine receptor stimulation such as hyperactivity and stereotypy. Furthermore, two recently synthesized drugs, TL-99 and (+) 3-PPP which have been claimed to have a selective agonistic action at dopamine autoreceptors induce yawning in rats. In addition, 6-OHDA lesions of the striatum abolish yawning induced by systemic apomorphine injection, indicating that the dopamine receptors involved in the production of the response are probably located pre-synaptically.

Considerable interest is now developing in dopamine agonist-induced yawning and the suggestion has been made that it can be used as a behavioural index of central dopamine autoreceptor stimulation. This suggestion is fully consistent with the evidence available from systemic drug administration studies and it is difficult to conceive of an alternative explanation of these data. The present data show that an identical yawning syndrome can be elicited by direct injection of dopamine agonists into the striatum. The most parsimonious explanation of these data is that yawning induced by central dopamine agonist injection is also autoreceptor mediated, particularly in view of the observation that a very low dose of haloperidol abolished yawning elicited by intrastriatal piribedil. However, this interpretation is speculative and the possibility of postsynaptic dopamine receptor mediation of the syndrome elicited by intracerebral application of piribedil and apomorphine cannot be ruled out because of the relatively large drug doses which were applied to the striatum to produce yawning. Further studies, incorporating central application of the putative autoreceptor agonists 3-PPP and TU 99 and the putative autoreceptor antagonist sulpiride are necessary to directly test the dopamine autoreceptor hypothesis. In addition, in vivo studies of striatal dopamine metabolism after dopamine agonist treatment using brain dialysis may prove extremely valuable in the investigation of dopaminergic involvement in yawning.

The muscarinic antagonist scopolamine inhibited yawning elicited by intrastriatal piribedil and therefore it appears that there is some cholinergic involvement in yawning. It has been claimed that yawning may be a consequence of the release of cholinergic neurones from inhibition by dopaminergic neurones. The present data are compatible with such a proposal. However, this hypothesis was not tested directly and further studies of the effects of central application of cholinergic agonists and antagonists (e.g., carbachol, scopolamine) should provide important information on the neural substrates of yawning.
-Banks RJ, Mozley L, Dourish CT. The angiotensin converting enzyme inhibitors captopril and enalapril inhibit apomorphine-induced oral stereotypy in the rat. Neuroscience. 1994;58(4):799-805  
-Stoessl AJ, Dourish CT, Iversen SD Apomorphine-induced yawning in rats is abolished by bilateral 6-hydroxydopamine lesions of the substantia nigra Psychopharmacol; 1987; 93; 336-342
-Stoessl AJ Effects of ageing on the behavioural responses to dopamine agonists: decreased yawning and locomotion, but increased stereotypy Brain Research 1989; 495; 20-30
-Stoessl AJ, Dourish CT, Iversen SD The NK-3 tachykinin agonist senktide elicits yawning and chewing mouth movements following subcutaneous administration in the rat. Evidence for cholinergic mediation. Psychopharmacology (Berl). 1988; 95; 4; 502-506
-Cooper SJ; Dourish CT Neural basis of drug induced yawning in neurobiology of stereotyped behaviour Oxford ed 1990
-Cooper SJ, Rusk IN, Barber DJ. Yawning Induced by the Selective Dopamine D2 Agonist N-0437 is Blocked by the Selective Doparnine Autoreceptor Antagonist (+)-UH 232. Physiol Behav. 1989;45:1263-1266
-Dourish CT, SJ Cooper Yawning elicited by sytemic and intrastriatal injection of piribedil and apomorphine in the rat Pyschopharmacology 1985; 86; 175-181
-Dourish CT, PH Hutson Bilateral lesions of the striatum induced with 6-hydroxydopamine abolish apomorphine-induced yawning in rats Neuropharmacology 1985; 24; 11; 1051-1055
-Collins G, JM Witkin et al Dopamine agonist-induced yawning in rats: a dopamine d3 receptor mediated behavior J Pharmacol Exp Ther 2005
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