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mise à jour du
14 août 2003
Eur J pharmacological
1983; 94; 271-280
Pharmacological characteristics of dopamine agonists on yawning behavior in rats
Protais P, Dubuc I, Constentin J
laboratoire de pharmacodynamie et pysiologie, faculté médecine Rouen, France


Introduction : Several reports have indicated that the reference DA agonist APO modulates yawning in rats in a biphasic manner; there is a dose-dependent induction of yawns for low doses of APO and a dose-dependent decrease of the yawning frequency for higher doses. Such a biphasic effect has been interpreted as the successive involvement of DA autoreceptors and postsynaptic DA receptors. According to this the lower doses of APO would stimulate DA autoreceptors and therefore decrease tonic doparninergic transmission with a consequent induction of yawning. On the contrary, the higher doses of APO, by stimulating postsynaptic DA receptors, would restore a high apparent level of the dopaminergic transmission associated with a disappearance of yawns. In fact, if other hypotheses could explain this biphasic effect, most would rest on the involvement of two subtypes of DA receptors differing by their relative sensitivity to APO. It was therefore of interest to check whether other known DA agonists belonging
-to various chemical classes displayed an activity similar to that of APO,
-to investigate the relative sensitivity to various neuroleptics of the DA receptors involved in the DA agonist-induced appearance and disappearance of yawns
-to consider the possible relationship between the Da agonist-induced disappearance of yawns and appreance of stereotypies.
Results concerning these three experimental steps are presented in this paper.
Discussion : We confirm the previous report (Holmgren and Urba-Holmgren, 1980; Yamada), that the reference DA agonist APO biphasically influences yawning in rats: yawns appear (YAWN APP.) at low doses and disappear (YAWN DIS.) at higher doses. DA receptors are clearly involved in these opposed effects of APO on yawning since YAWN APP. and YAWN DIS. were produced by all the purported DA agonists tested and were affected by most of the neuroleptics tested. This biphasic effect was also observed when the time course of yawning induced by 0. 15 mg - kg APO was considered. This time-dependent dual effect and the biphasic dose-response curve seem connected with the brain concentration of APO. Whereas the yawning frequency was highest at the beginning and end of the observalion period i.e. when the brain concentration of APO was low, the yawning frequency was low in the middle of the observation period i.e. when the brain concentration of APO was highest. The variations in the brain concentration of DA agonists might account, al least in part, for the higher frequency of yawns observed with bromocriptine. This drug has a relatively long half-life and crosses the blood brain barrier with difficulty so that an optimal and stable brain concentration could be obtained for the induction of yawns during the whole period of observation.
All the neuroleptics tested antagonized APO-induced YAWN APP. Furthermore, increasing doses of most of the neuroleptics (i.e. haloperidol, chlorpromazine, mezilamine, thioridazine and metoclopramide) made yawning behaviour reappear (YAWN REAPP.) in animals treated with 0.6 mg -kg, APO. YAWN REAPP. likely resulted from the blockade of the DA receptors involved in YAWN DIS. with a persistent stimulation of the DA receptors mediating YAWN APP. For these neuroleptics, the apparent ID50 for the antagonisrn of APO-induced YAWN DIS. were similar to those obtained for the antagonism of YAWN APP. In addition, at 0.6 mg -kg, the APO brain concentration was approximately 6 fold that at which there was apparent maximal stimulation of the DA receptors involved in YAWN APP. (0.1 APO).
Therefore, it seems that the agonist/antagonist concentration ratio favours the prevalent action of APO on the DA receptors involved in YAWN APP. This is supported by the fact that yawns decreased then were suppressed when the doses of haloperidol were further increased. So il appears that, in 0.6 mg - kg APO-injected rats, the response to increasing doses of haloperidol followed the bell-shaped doseresponse curve of APO in the opposite direction.
In contrast, increasing doses of clozapine and of some benzamide neuroleptics (sulpiride, veralipride and DAN 2163) were unable to produce YAWN REAPP. in 0.6 mg -kg APO-injected rats. The lack of YAWN REAPP. with clozapine was probably due to its antimuscarinic properties since antimuscarinic agents oppose APO-induced yawns. The antimuscarinic activity of clozapine is shown by the antagonism of physostigmine-induced yawns by a low dose of this drug (about twice its ID50 on 0.1 mg - kg APO-induced yawns). It is then possible to consider that stimulation of the DA receptors involved in YAWN APP. occurs in rats treated with clozapine and 0.6 mg - kg APO but that the effect of their stimulation is simultaneously suppressed at cholinergic synapses.
Similar results would be obtained with other drugs displaying more antimuscarinic than antidopaminergic activity. This does not seem to be the case for thioridazine which induced YAWN REAPP. in 0.6 mg - kg - 1 APO-injected rats and hardly antagonized physostigmine-induced yawns. The lack of YAWN REAPP. with sulpiride, veralipride and DAN 2163 does not seem to have the same meaning. Antimuscarinic activity is ruled out since antagonism of physostigmine-induced yawns was obtained neither with sulpiride nor, under similar conditions, with veralipride and DAN 2163 (unpublished data). Also, it has not yet been reported that benzamides might share other pharmacological properties able to influence yawning in the same way as antimuscarinic drugs. That systemically injected benzamides modified, relatively to other neuroleptics, the access or the regional distribution of APO in the brain could explain their peculiar effects on yawning. However, this interpretation is unlikely to be correct since similar results were also found following inj iv. administration (unpublished data). Therefore, whereas the neuroleptics which induced YAWN REAPP. in 0.6 mg - kg APO-injected rats had similar ID50 on both APO-induced YAWN APP., YAWN DIS. and sniffing, sulpiride, veralipride and DAN 2163 antagonized APO-induced YAWN APP. at doses niarkedly lo\ver than those at which they opposed APO-induced sniffing. The ratio of their ID50 (sniffing/yawning) was between 3 (sulpiride) and 22 (veralipride). Thus, the lack of YAWN REAPP. established with sulpiride, veralipride and DAN 2163 in 0.6 mg -kg APO-injected rats suggests that, as DA agonists, these benzamides would recognize ln a differentiated manner the DA receptors involved in YAWN APP. and YAWN DIS. respectively.
In this view, the DA receptors mediating YAWN APP. would display a high relative sensitivity for DA agonists and would be blocked by low doses of all neuroleptics, either the 'classical' or the 'atypical' ones, including the three above benzamides. In contrast, the DA receptors mediating YAWN DIS. would display a low relative sensitivity for DA agonists and would be blocked by low doses of neuroleptics, except sulpiride, veralipride and DAN 2163. The pharmacological characteristics of the latter DA receptors appear similar to those of the receptors mediating APO-induced sniffing. These data may be compared with the ability of sulpiride and DAN 2163 to distinguish between the D-2 and D-4 subtypes of DA binding sites (Sokoloff et al., 1980; Schwartz et al., 1983). The property of sulpiride, veralipride and DAN 2163 to discriminate between two DA receptor subtypes is not common to all the benzamide neuroleptics since it is not shared by metoclopramide.

In the same range of doses as for yawning, DA agonists modulate in a biphasic manner other effects such as climbing locomotor activity , penile erections or EEG activity. These biphasic effects have generally been interpreted as the consequence of the action of DA agonists at the same synapses: whereas low doses of DA agonists would stimulate autoreceptors, higher doses would stimulate postsynaptic receptors. Such an interpretation was also suggested for yawning. The easy antagonism of 0.1 mg - kg - 1 APO-induced YAWN APP. by sulpiride could be consistent with this hypothesis since DA autoreceptors seem to have a relatively high affinity for this drug.

However, as an alternative it may be suggested that yawning and sniffing would be mutually exclusive. This hypothesis is supported
- by the similar FD50 of DA agonists on YAWN DIS. and the induction of sniffing,
- the similar ID,, of Inost DA antagonists to oppose YAWN DIS. and sniffing,
- the opposite development of the time courses of 0. 15 mg - kg APO-induced yawning and sniffing
- the hypersensitivity to APO of sniffing observed concomitantly with hypersensitivity to APO-induced YAWN DIS. in rats with 6-hydroxydoparnine-lesioned olfactory tubercles. Moreover, the decreased yawning frequency observed in this latter condition does not seem connected with the disappearance of DA autoreceptors resulting from the dopaminergic denervation of olfactory tubercles since DA neurons projecting to the septum are thought to be involved in yawning.
Therefore, the lack of YAWN REAPP. in rats injected with 0.6 mg - kg APO that we observed with ( ± )- or ( - )-sulpiride, veralipride and DAN 2163 (at doses for which these benzamides antagonized sniffing) could depend on the ability of these drugs to distinguish between the DA receptors involved in YAWN APP. and in sniffing.
In conclusion, the antagonism byneuroleptics of 0.1 mg -kg APO-induced yawning and the effects of increasing doses of these drugs on both sniffing and yawning in 0.6 mg - kg APO-injected rats may be indicative of the property of DA antagonists to distinguish between two DA receptor subtypes. Ilowever, anticholinergic activity of these agents must then be simultaneously excluded.
  1. -Protais P, Dubuc I, Constentin J Pharmacological characteristics of dopamine agonists on yawning behavior in rats. Eur J pharmacological 1983; 94; 271-280
  2. -Protais P, Dubuc I, Colboc O, Costentin J Étude des récepteurs dopaminergiques dont la stimulation induit ou inhibe les bâillements chez le rat. J Pharmacologie 1982; sup1; 191
  3. -Protais P, Windsor M, Mocoer E, Comoye E Post-synaptic 5-HT1A receptor involvmement in yawning and penile erections induced by apomorphine, physostigmine and MCPP, in rats Psychopharmacology 1995; 120; 4; 376-383