mise à jour du
8 mai 2003
1986; 89; 259--260  
Antagonism of apomorphine-induced yawning by SCH 23390: Evidence against the autoreceptor hypothesis
M. Morelli, R. Longoni, L. Spina, and G. Di Chiara
Institute of Experimental Pharrnacology and Toxicology,
University of Cagliari Italy


It has been recently suggested that the yawning syndrome (YWG) elicited in rats by low doses of dopamine (DA) receptor agonists is due to stimulation of DA-autoreceptors (Gower et al. 1984; Stahle and Ungerstedt 1984). An antagonist of DA receptors has recently became ovailable, the benzazepine SCH 23390 (Hyttel 1984), which has affinity for D-1 receptors about 3 orders of magnitude higher than for D-2 receptors. Since DA autoreceptors are of the D-2 type (Hyttel 1984), SCH 23390 is not expected to interact with DA autoreceptors at concentrations sufficient to block D-1 receptors; in fact SCH 23390 is a very poor antagonist of putative DA autoreceptor-mediated effects both in vitro and in vivo (Hyttel 1984, Gessa et al. 1985). We now report that apomorphine-induced YWG is potentiated by a 16 h depletion of central catecholamine stores with reserpine and is blocked both in normal and reserpine-pretreated rats by low doses of SCH 23390,

Materials and methods

Male Sprague-Dawley rats (Charles River, Italy) of 180-200 g were administered reserpine (Serpasil, Ciba) at a dose of 5.0 mg/kg IP and 16 h thereafter the rats showing the typical reserpine syndrome consisting of palpebral ptosis, sedation and hunched-back posture were selected and transferred to Perspex testing cages (40 x 25 x 15 cm bigh). Control rats were given saline (0.2 rni/kg IP) in place of reserpine. After a 60-min adaptation period, the rats were pretreated SC in the flank with saline (0. 1 ml/1 00 g) or with 0.05 mg/kg SCH 23390 (kindly provided by Dr. Ongini, Essex-Schering, Italy) dissolved in saline. Fifteen minutes later the rats were injected SC in the neck with different doses of apomorphine and the number of yawnings with or without stretching was recorded during 45 min of observation. ED5O with 95% confidence limits were calculated by logprobit analysis. Significant differences were determined by two-tailed Student's t-test following ANOVA.

Results and discussion

Apomorphine showed a bell shaped dose-effect curve for YWG in normal and reserpinized rats. In fact, as shown in Table 1, in normal and reserpinized rats apomorphine maximally stimulated YWG at doses of 0.080 and 0.025 mg/kg SC, respectively, with lower or higher doses being less effective. After doses higher than 0.025 mg/kg SC in reserpinized rats and higher than 0.080 in normal rats YWG was replaced by stereotyped hypermotility and sniffing. The ED50 (dose of apomorphine in mg/kg SC eliciting at least ten yawnings in 50% of the rate) with 95% confidence limits (in parentheses) was 0.015 (0.09-0.022) in reserpinized rats and 0.063 (0.042-0.094) in non-reserpinized rats. Pretreatment with 0.05 mg/kg SC SCH 23390 effectively antagonized YWG induced by low doses of apomorphine both in normal and in reserpinized rats (Table 1). After doses of apomorphine higher than those maximally effective in inducing YWG, SCH 23390 pretreatment apparently facilitated YWG. After SCH 23390 pretreatment the ED50 (wiht 95% confidence limits) of apomorphine for YWG in normal and in reserpinized rat was, respectively, 0.38 (0.25-0.57) and 0.084 (0.056-0.126).

This study shows that the ED50 for apomorphine-induced YWG is significantly lowered, as indicated by the non-overlapping 95% confidence limits, by a 17-h depletion of catecholamine stores with reserpine and is significantly increased by pretreatment with a low dose of SCH 23390 in normal and in reserpine-pretreated rats. These results indicate that 17-h reserpine pretreatment potentiates wthe ability of apomorphine to induce YWG while SCH 23390 pretreatment blocks it. The ability of a 17-h reserpine pretreatment to potentiate apomorphine-induced YWG appears analogous to the potentiation of apomorphine stereotypy induced by reserpine pretreatment and can be explained as post-synaptic supersensitivity consequent to the reserpine-induced interruption of DA transmission (Di Chiara and Gessa 1978). The ability of SCH 23390 to block apomorphine-induced YWG in reserpinized rats is in keeping with a post-synaptic origin of this behavioural syndrome; in fact SCH 23390, at low doses, is expected to be devoid of effects on D-2 receptors in general (Hyttel 1984) and on DA autoreceptors in particular both in vitro (Hyttel 1984) and in vivo (Gessa et al. 1985).

The finding that SCH 23390 reduced apomorphine-induced YWG also in reserpinized rats is in agreement with the observation that SCH 23390 potently blocks apomorphine stereotypy not only in normal rats but also in rats pretreated with reserpine (Arnt 1985; Breese and Mueller 1985). Since SCH 23390 seems to acquire in vivo D-1 specificity after 24-h reserpine-a-methyltyrosine-induced depletion of catecholamines (Breese and Mueller 1985), our observation could be interpreted to indicate that D-1 receptors contribute to the YWG induced by apomorphine in reserpinized rats.

The observation that SCH 23390 facilitates YWG after high doses of apomorphine can be explained if one considers that these doses are in the descending part of the bellshaped dose-response curve for apomorphine-induced YWG. At these doses of apomorphine, the expression of YWG is reduced as a result of the emergence of competing behavioural items (locomotion, sniffing). Accordingly, the ability of SCH 23390 to potentiate YWG at high doses of apomorphine is a reflection of an overall shift to the right of the bell-shaped dose-response curve for apomorphineinduced YWG which in turn might be the result of the DA-receptor blockade by SCH 23390.

Our results directly contradict the hypothesis that apomorphine produces YWG by acting on DA autoreceptors. In fact, if this hypothesis were true, reserpine pretreatment would have abolished the ability of apomorphine to induce the behaviour and SCH 23390, in view of its D-1 specificity, would have been ineffective at low doses. Indeed, the autoreceptor hypothesis of DA agonist-induced YWG is based solely on the fact that this behaviour is evoked by low doses of DA agonists and is blocked by (-)sulpiride at doses which are considered specific for DA autoreceptors (Gower et al. 1984; Stahle and Ungerstedt 1984). It is conceivable, however, that the same dose of DA agonist could elicit DA autoreceptor-mediated effects or post-synaptic effects depending on the baseline activity of the animals; indeed low doses of apomorphine elicit hypomotility and sedation in rats exposed to a novel environment (Di Chiara and Gessa 1978) while inducing YWG in well adapted rats.

The effectiveness of (-)sulpiride as an antagonist of apomorphine YWG (Stahle and Ungerstedt 1984) simply indicates that this effect is at least in part mediated by D-2 receptors but does not allow any conclusion on their location. The ability of SCH 23390 to block apomorphine-induced YWG suggests that not only D-2 receptors but also D-1 receptors can be operative in eliciting this behavioural syndrome. Therefore, blockade of DA agonist-induced YWG is a further addition to the list of those effects of SCH 23390 like sedation, hypomotility and catalepsy (Morelli and Di Chiara 1985), blockade of conditioned avoidance responding, blockade of DA-agonist induced hypothermia (Carboni et al. 1986) and stereotypy, which were previously considered as typical of D-2 antagonists. IC as it seems, these effects are due primarily to blockade of D-1 receptors by SCH 23390 we should conclude that the central functions of D-1 receptors are largely superimposable to those of D-2 receptors or/and that a certain degree of D-1 receptor stimulation is essential for the full behavioural expression of D-2 receptor activation.

Gessa GL Stretchings and yawnings induced by adrenocorticotrophic hormone Nature 23/07/1966; 5047; 426-427
Gessa GL Stretching and yawning movements after intracerebral injection of ACTH Revue Canadienne Bioliologie; 1967, 26, 3, 229-236
Hipolide DC, Lobo LL, De Medeiros R, Neumann B, Tufik S Treatment with dexamethasone alters yawning behavior induced by cholinergic but not dopaminergic agonist Physiol Behav 1999; 65; 4-5; 829-32
Kimura H, Yamada K, Nagashima M, Matsumoto S, Ishii Y, Yoshida S, Fujii K, Furukawa T Role of adrenergic neuronal activity in the yawning induced by tacrine and NIK-247 in rats. Pharmacol Biochem Behav 1992; 43; 4; 985-91
Kimura H, Yamada K, Nagashima M, Furukawa T Involvement of catecholamine receptor activities in modulating the incidence of yawning in rats.Pharmacol Biochem Behav 1996; 53; 4; 1017-21
Laing J, Ogilvie R EEG correlats of yawning during sleep onset Sleep Research 1988; 17; 98
Lobo LL, Neumann BG, Eidman DS, Tufik S Effects of REM sleep deprivation of ACTH-induced yawning. Pharmacology 1990; 40; 3; 174-8
Lynch MR Dissociation of autoreceptor activation and behavioral consequences of low doses apomorphine treatment Prog Neuro-Psychopharmacol & Biol Psychiat 1991; 15; 689-698
Molgilnicka E REM sleep deprivation changes behavioral response to catecholaminergic and serotoninergic receptor activation in rats Pharmacol Biochem Behav 1981; 15; 1; 149-151
Morelli M et al Antagonism of apomorphine-induced yawning by SCH 23390: Evidence against the autoreceptor hypothesis
Serra G , Collu M and Gessa GL Yawning is elicited by D2 dopamine agonists but is blocked by D1 antagonist Psychopharmacology 1987; 91; 330-337
Serra G, Gessa GL Hypophysectomy prevents yawning and penile erection but not hypomotility induced by apomorphine Pharmacology Biochemistry & Behavior 1983; 19; 917-919
Serra G et al Cycloheximide prevents apomporphine induced yawning, penile erection and genital grooming in rats European Journal of Pharmacology 1983; 86; 279-282
Stahle L Do autoreceptors mediate dopamine agonist-induced yawning and suppression of exploration ? a critical review. Psychopharmacology 1992; 106; 1-13
Stahle L, Ungerstedt U Yawning and suppresssion of exploration induced by dopamine agonists: no relation to extracellular strital levels of dopamine Pharmacol Biochem Behav1990; 35; 201-209
Stahle L, Ungerstedt U Assessment of dopamine autoreceptor agonist properties of apomorphine, (+)3ppp and (-)3ppp by recording of yawning behaviour in rats Europ J Pharmacol 1984; 98; 307-310
Neumann BG, Troncone LR, Braz S, Tufik S Modifications on dopaminergic and cholinergic systems induced by the water tank technique: analysis through yawning behavior Arch Int Pharmacodyn Ther 1990; 308; 32-8
Tufik S Does REM sleep deprivation induce subsensitivity of presynaptic dopamine or postsynaptic acetylcholine receptors in the rat brain? European Journal of Pharrnacology 1987; 140; 215-219
Tufik S Effects of stress on drug induced yawning Physiology & behavior 1995; 8; 1; 1881-18
on drug induced yawning Physiology & behavior 1995; 8; 1; 1881-18