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mise à jour du
26 février 2006

Effects of apomorphine, TL-99 and 3-PPP
on yawning in rats
Mogilnicka E, Boissard CG, Delini-Stula A.
Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland


Abstract : Dopaminergic agonists, apomorphine (APO) (0.025-0.25 mg/kg, s.c.), TL-99 (0.5-3 mg/kg, s.c.) and 3-PPP (0.15-10 mg/kg, s.c.) elicited yawning in rats and the dose-response curves of all 3 compounds showed a bell-shaped form. Haloperidol (0.02 mg/kg, s.c.) reduced the yawning induced by DA-agonists to about 50%. The potencies of the DA-agonists in inducing yawning were APO greater than TL-99 greater than 3-PPP (comparable to potencies obtained in other in vivo tests, determining DA-ergic activity). The findings support the validity of the yawning phenomenon as a screening test for DA-agonists. Additionally, it was found that apomorphine induced yawning was significantly and dose-dependently enhanced by the beta-agonist, formoterol. This effect was counteracted by scopolamine, not changed by metergoline and further increased by l-propranolol. These data support the hypothesis of cholinergic involvement in yawning and indicate a role, though unclear at present, of beta-receptors in this behaviour.

Recently, it was shown that after administration of relatively small doses of different dopaminergic (DA) agonists, characteristic yawning behaviour (YN) appeared in rats. It was suggested that this symptom could be useful in the screening of drugs (Mogilnicka and Klimek, 1977). The mechanism of yawning behaviour is still unclear, however the investigations of Urba-Holmgren, Gonzales and Holmgren (1977) and Yamada and Furukawa (1980) have pointed to the involvement of the cholinergic system in this behaviour. The cholinergic drugs, physostigmine and pilocarpine, induce yawning behaviour which is abolished by scopolamine. Scopolamine also completely inhibited yawning induced by small doses of apomorphine indicating that apomorphine-induced yawning can result from secondary activation of cholinergic neurones. Assuming that small doses of apomorphine produce an inhibition of DA-release from presynaptic sites, resulting in activation of cholinergic neurones (Carlsson, 1975; Chiara, Porceddu, Vargiu, Argiolas and Gessa, 1976), Yamada and Furukawa (1980) suggest that apomorphine elicits yawning by stimulating presynaptic DA-receptors and that DA-ergic inhibition and cholinergic activation are concomitantly involved in yawning behaviour. Larger doses of apomorphine, stimulating postsynaptic DA-receptors, induce hyperactivity and stereotyped behaviour which mask yawning, so it could be expected that DA-receptor agonists, deprived of this activity, should produce yawning over a wide range of doses. The effects of apomorphine were compared with those of two recently-described DA-agonists, TL-99 (6,7-dihydroxy-2-piperidine) and 3-PPP (N-n -propyl-3-(3-hydroxyphenyl)-piperidine) which have been reported to possess selective agonistic action at presynaptic DA-receptors (Hjorth, Carisson, Wilkstrôm, Lindberg, Sanches, Hacksell, Arvidsson, Svensson and Nilson, 1981; Goodale, Rusterholz, Long, Flynn, Walsh, Cannon and Lee, 1980). It must be added however, that in spite of the fact that TL-99 and 3-PPP do not induce typical stereotyped behaviour, their postsynaptic DAagonistic properties have been demonstrated in other pharmacological models (Martin, Haubrich and Williams, 1980). Very recently, using a binding assay, Williams and Totaro (1983) showed preferential interaction between 3-PPP and TL-99, and postsynaptic, rather than presynaptic [3H]-APO-binding sites in striatal membrane of rats.
There have been reports indicating that beta-adrenergic receptors contribute to the regulation of DA-transmission (Reisine, Chesselet, Lubezki, Chéramy and Glowinski, 1982), as some clinical studies have indicated that propranolol and other J3-adrenergic receptor blockers may be of use in the treatment of schizophrenia (Elizur, Segal, Veret, Davidson and Atsmon, 1979; Lindstrom and Persson, 1980). Therefore, in the second part of these experiments, the possibility that beta-agonists could have an influence on the apomorphine induced yawning was investigated.
As described earlier apomorphine, a DA-agonist in a small dose, induced yawning in rats and this behaviour was reduced by DA-receptor blockade with neuroleptics (Dubuc, Protalis, Colboc and Constentine, 1982; Mogilnicka and Klimek, 1977). Recently it was found that haloperidol reduced yawning induced by apomorphine in doses much smaller than those needed for inhibition of stereotypy or hyperactivity (Dubuc et al., 1982; Nickolson and Berendsen, 1980) which led to the suggestion that yawning induced by apomorphine is mediated by DA-autoreceptors. This conclusion is also supported by present results, which show that the compounds TL-99 and 3-PPP, thought to be putative DAautoreceptor agonists, induced yawning and that this behaviour was reduced by relatively small dose of haloperidol. These agents, in contrast to apomorphine did not induce hyperactivity or stereotypy at any dose level, which indicates that TL-99 and 3-PPP do not stimulate postsynaptic DA receptors, responsible for this behaviour. Consequently, yawning cannot be mediated by the same receptors.
In the respect of potency for inducing yawning (dose-ranges) apomorphine was stronger than TL-99 and 3-PPP. It should be noted also that the relationship is similar to that observed in other in vivo models, such as inhibition of motility, circling behaviour (in 6-OH-DA-lesioned rats) as well as emetic effects in dogs (Arnt, Christensen, Hyttel, Larsen and Svendson, 1973; Martin et al., 1981). This suggests that the DA-receptors which mediate yawning are similar to those leading to the behavioural responses mentioned above.
It seems likely, that if in a screening observation a given substance induces yawning in rats (which is blocked by DA-antagonists), there is a high probability that the compound possesses DA-receptor agonistic properties (it must be emphasized also that subcutaneous administration of DA-agonists is more efficient than intraperitoneal administration in inducing yawning). It is known that yawning in rats can be induced by muscarinic stimulants (Urba-Holmgren et al., 1977; Yamada and Furukawa, 1980). However, if DA-antagonists block drug-induced yawning, direct muscarinic stimulation can be almost excluded, since neuroleptics (except those having an anticholinergic component) do not abolish the yawning induced by physostigmine (Dubuc et al., 1982).
As has been mentioned, the existing data indicate a significant, activating role of the muscarinic system in yawning. Yamada and Furukawa (1980) suggest that apomorphine elicits yawning via indirect activation of cholinergic neurones. Recently, the effects of different DA-agonists, including TL-99 and 3-PPP on striatal levels of acetyicholine (ACh) were investigated over a wide dose-range (Waldmeier, 1983). By comparing the dose-ranges of DA-agonists, influencing levels of ACh with those inducing yawning, it was observed that yawning appeared in ranges which paralleled increased (not decreased) ACh levels. Thus, it can be speculated that yawning can be mediated by DA-receptors (postsynaptic?) which are responsible for an increase of striatal ACh and not by presynaptic receptors (i.e. those reducing DA-ergic transmission and thus leading to an increase of ACh release and consequently a decrease in the level of ACh).
Another finding of the present study is that beta-agonists influenced apomorphine-induced yawning. Formoterol, a beta2-agonist as well as prenalterol, a beta1-agonist, increased apomorphine-induced yawning. The lack of action of another beta2-agonist, clenbuterol, is difficult to explain at present; however, pretreatment with clenbuterol provoked more stereotypy-like behaviour in rats injected with apomorphine. The sniffing, chewing and eating of saw dust covering the cage bottom, may mask the increase in yawning.
Recently it was described that beta-agonists enhanced behavioural responses mediated by 5-hydroxytryptophan (5-HTP) (Cowen, Grahame-Smith, Green and Heal, 1982) and also a role for the 5-HT-system in the yawning phenomenon was postulated (Marini, 1981). However the facilitation of apomorphine-induced yawning produced by formoterol was not counteracted by metergoline, a 5-hydroxtryptamine (5-HT) receptor antagonist. The fact that scopolamine blocked epidoses of yawning in rats treated with apomorphine as well as apomorphine plus formoterol points to a possible muscarinic component in the potentiation induced by fi-agonists. Indeed the enhancement of [3HI-QNB binding in the striatum of rats by the beta-adrenergic agonist iso-proterenol has been observed (Ehlert, Roeske and Yamamura, 1981). Formoterol-induced potentiation of yawning induced by apomorphine was not abolished by the fbeta-blocker, l-propranolol; on the contrary, yawning was further enhanced. l-Propranolol, by itself potentiated yawning induced by apomorphine and this effect seemed to be additive to the action of formoterol. The fact that both beta-receptor stimulation and blockade produced the same facilitating effect on apomorphine-induced yawning is confusing. It is not possible at present either to explain this phenomenon or to derive any conclusions about the role of beta-receptors in yawning. Nevertheless, yawning, although the mechanism is still unknown, seems to be a reliable behavioural sign of the DA-agonistic action of drugs.
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