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mise à jour du 29 mai 2003
Antagonism of the apomorphine-induced yawning by atypical neuroleptics
I Dubuc, P Protais, 0 Colboc, J Costentin
Laboratoire de Pharmacodynamie et Physiologie,
U.E.R de Médicine et Pharmacie de Rouen, France


The almost fortuitous discovery of antipsychotic agents which are devoid of cataleptogenic activity in rats has led to a search for tests which will easily screen for these drugs, called "atypical" neuroleptics. It is hoped by such tests to select antipsychotic drugs which do not cause extrapyramidal symptoms in man. Some of these tests have been reported previously: the antagonism in mice of apomorphine-induced climbing behaviour (Protais Costentin and Schwartz, 1976), the potentiation of morphine-induced catalepsy in rats or the conversion of the running fit elicited in mice by morphine into a marked hypokinesia (Barghon, Protais, Colboc and Costentin, 1981). With the view to developing other tests, attention was directed to the various behavioural effects of apomorphine, in order to see which of them were antagonized by "atypical" neuroleptics. An antagonism by these drugs of apomorphine-induced yawninq is reported here.

METHODS : Male Wistar rats (IFFA CREDO), weighing 200-250 g were used. They were housed in a well-ventilated room at an ambient temperature of 220C and under artificial illumination (light on between 8 a.m. and 8 p.m.) The rats were separated without food in wire mesh cages (L = 25 cm, W = 18 cm, H = 30 cm) as soon as the neuroleptics agents were injected For testing, the animals were injected subcutaneously with either apomorphine or physostigmine, and the yawns they displayed during the following 60 min were counted. The mean number of yawns of each group was compared with that of the respective control group by use of Student's t test.

RESULTS AND DISCUSSION :As described by Holmgren and Urba-Holmgren (1980), increasing doses of apomorphine modified the number of yawns occurring in rats in a biphasic manner: durinq the 60 min. following a subcutaneoys injection of apomorphine the number of yawns increased from 12.5 µ to 100 µ of apomorphine then decreased (the yawns disappearing at a dose of approximately 600 µ Using 100 µ of apomorphine, some neuroleptic drugs, especially "atypical" ones, were tested, determining whenever possible their ID50. Whereas domperidone, a dopamine antagonist known not to pass the bloodbrain barrier, was ineffective in doses up to 0.5 the classical neuroleptic haloperidol and the four best known "atypical" neuroleptics were effective antagonists in relatively small doses.

Considering the biphasic aspect of the dose-response curve for apomorphine, in order to determine whether the neuroleptic-induced disappearance of yawns in animals treated with 100µ of apomorphine resulted from a true antagonism or, conversely, from a potentiation of its action, the effect of the ID50 of these neuroleptics, opposed to a smaller test dose of apomorphine (50 ) wai determined. Whereas in the animals treated only with apomorphirie (50 µ , s.c.) the number of yawns was similar to the preceding one, ie. 11.7 ± 2.0 (mean ± S.E.M. of 12 animals), it was 2.9 ± 0.9 in haloperidol-pretreated rats (mean ± S.E.M. of 8 animals, P < 0.01), 3.2 ± 1.4 in sulpiride-pretreated rats (mean ± S.E.M. of 9 animals, P < 0.01, 5.3 1.5 in thioridazine-pretreated rats (mean ± S.E.M. of 8 animals, P < 0.05), 3.0 ± 2.0 in clozapine-pretreated rats (mean ± S.E.M. of 8 animals, P < 0.02) and 4.0 ± 1.0 in mezilamine-pretreated rats (mean ± S.E.M. of 8 animals, P < 0.02). In addition, pretreatment of the rats with increasing doses of sulpiride only caused a d?se-dependent inhibition of the yawning behaviour elicited by either 25 µ or 100 µ of apomorphine. Therefore it may be concluded that an antagonism was observed, and not a potentiation.

The antagonism by classical neuroleptics is well documented, particularly for fluphenazine (Yamada and Furukawa, 1980), spiperone (Holmgren and Urba-Hol:mgren, 1980), butaclamol and pimozide (Mogilnicka and Klimek, 1977) but has not been considered here (except for haloperidol).

A dopaminergic-cholinergic link has been shown to be involved in yawning behaviour (Yamada and Furukawa, 1980; Holmgren and Urba-Holmgren, 1980) such that central muscarinic receptor blocking agents oppose the yawning caused by dopamine agonists. The absence of cataleptogenic activity by clozapine has been claimed to depend on its anticholinergic properties, correcting the extrapyramidal symptoms resulting from the blockade of dopamine receptors. Such a dual action, ie. antidopaminergic and anticholinergic, would not limit the yawning test since it would lead to an increase in the antagonism of apomorphine-induced yawning.

In similar conditions to those used previously, but this time using the cholinomimetic drug physostigmine (75 µ , s.c.) to induce yawns, the possibility that anticholinergic properties of the "atypical" neuroleptics were involved in the antagonism of apomorphine-induced yawning, was tested. For this the neuroleptics were tested at doses corresponding to approximately twice the ID50s.

The physostigmine-induced was not decreased to a significant extent (P 0.05) ln rats pretreated with haloperidol, mezilamine, sulpiride or thioridazine. However, the latter drugs, which is known to possess anticholinergic activity, was an effective antagonist when tested in a dose corresponding to 5 times it ID50 in the apomorphine-induced yawning behaviour test. Finally, clozapine, in a dose corresponding to its ID50 for apomorphine-induced yawning behaviour, induced a clear antagonism which was complete for twice this dose (Fig. 2). Therefore it appears that only with clozapine was an strong anticholinergic component involved in the suppression of apomorphine-induced yawning. However, this does not contradict the well-known anticholinergic properties of thioridazine (Miller and Hiley, 1974), but only indicates that for doses at which the dopamine receptors involved in yawning were blocked, the cholinergic receptors relaying the apomorphine effect were virtually not blocked. This is in agreement with the relative anticholinergic and antidopaminergic activity reported from binding studies by Laduron and Leysen (1978) .

This dopamine-acetylcholine interaction shows that the inhibition of apomorphine-induced yawning would not provide a specific methods for screening neuroleptics, since it could lead to the selection of agents having only the central anticholinergic activity and possibly other drugs interacting with other neurotransmitters. However, the present approach, combining the antagonism of yawning elicited by apomorphine and by physostigmine, could be of interest to extend investigations of neuroleptics, and particularly ..atypical" ones, after their selection by the use of other tests, such as the climbing test (Protais et al., 1976; Marcais, Protais, Costentin and Schwartz, 1978). In fact, antimus«E-arinic agents potentiate apomorphine-induced climbing behaviour (unpublished data), whereas they antagonize apomorphine-induced yawning; therefore these approaches seem complementary.


  1. Barghon, R., Protais, P., Colboc, 0. and Costentin, J. (1981). Hypokinesia in mice and catalepsy in rats elicited by morphine associated with antidopaminergic agents, incl uding atypi cal neuroleptics . Neurosciences Lett. 27:69.
  2. Holmgren, B. and Urba-Holmgren, R. (1980). Interaction of cholinergic and dopaminergic influences on yawning behaviour. Acta Neurobiol Exp. .10 : 6 3 3
  3. Laduron, P.M. and Leysen, J.E. (1978). Is the low incidence of extrapyramidal side-effects of antipsychotics associated with antimuscarinic properties? J.Pharm.Pharmacol 30:120.
  4. Marcais, H., Protais, P., Costentin, J. and Schwartz, J.C. (1978). A gradual score to evaluàte the climbing behaviour elicited by apomorphine in mice. Psychopharmacology, 5 6 : 2 3 3 .
  5. Miller, R.J. and Hiley, C.R. (1974). Anti-muscarinic properties of neuroleptics and drug-induced Parkinonsism. Nature 248:596.
  6. Mogilnicka, E. and Klimek, V. (1977). Drugs affecting dopamine neurons and yawning behaviour. Pharmacol Biochem. and Behav., 7:303.
  7. Protais, P. Costentin, J. and Schwartz, J.C. (1976). Climbing behaviour induced by apomorphine in mice: a simple test for the study of dopamine receptors in striatum. Psychopharmacology, 50:1.
  8. Yamada, K. and Furukawa, T. (1980). Direct evidence for involvement of dopaminergic inhibition and cholinergic activation in yawning. Psychopharmacology, 6 7 : 39.
-Tang AH, Himes CS Apomorphine produced more yawning in Sprague-Dawley rats than in F344 rats: a pharmacological study Eur J Pharmacol 1995; 284; 1-2; 13-18