mise à jour du
1 janvier 2011
Eur J Pharmacol.
Yawning produced by dopamine agonists in rhesus monkeys
Robert A. Code and Andrew H. Tang
CNS Research, The Upiohn Company, Kalamazoo, U.S.A


Yawning was recorded from five rhesus monkeys restrained in a chair after i.m. injection of dopaminergic compounds: apomorphine (0.03 mg/kg), quinpirole (0.01 mg/kg), and (-)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (1 mg/kg). SKF 38393 or physostigmine produced no yawning. Yawning from apomorphine was blocked by chlorpromazine or SCH 23390 (0.03 mg/kg). Sulpiride (10 mg/kg) was ineffective. The difference between rats and monkeys in their yawning response to dopaminergic compounds is discussed.
1. Introduction
Dopamine agonists, such as apomorphine, produce yawning in rats and humans. The pharmacology of this phenomenon in rats has been extensively studied. The dose-response relationship is biphasic, with the optimal dose for yawning always below that to elicit stereotypic behaviors and the order of potency, among the agonists, correlates with that of dopamine autoreceptor activation using biochemical endpoints (Gower et al., 1984). There is, however, no direct evidence relating the yawning response to dopamine autoreceptor stimulation. The time course of yawning after an injection of apomorphine is also different from that of the reduction of striatal extracellular dopamine level as expected from dopamine autoreceptor activation (Stahie and Ungerstedt, 1990).
The role of the dopamine D, receptor in the yawning response to dopamine agonists in rats is a matter of controversy. The D1-selective partial agonist, SKF 38393, produces no yawning when given alone. But, both antagonism (Zarrindast and Poursoltan, 1989;) and potentiation (Spina et al., 1989) by SKF 38393 on ciopantinergic yawning in rats have been reported. Likewise, antagonism of dopaminergic-induced yawning in rats by SCH 23390, a selective D1 antagonist, was found by some investigators (Morelli et al., 1986), but not others (Zarrindast and Poursoltan, 1989). Mixed
dopamine DJ/D, antagonists (neuroleptics) are generally effective blockers of dopaminergic-induced yawning in rats (Dubuc et al., 1982).
A limited study of dopaminergic-induced yawning in human subjects indicates that it occurs at sub-emetic doses (LaI, 1988). We are not aware of any similar study in subhuman primates. This study investigates dopaminergic-induced yawning in rhesus monkeys.
2. Materials and methods
 2.1. Animals
Each compound was studied in five adult rhesus monkeys. All but one (monkey No. 659) are males. The animals were selected for their calm behavior when restrained in a chair and for their yawning response to apomorphine in an initial screening test. Between experimental sessions, the monkeys were housed in individual cages, with room lighting at a 06:00-18:00 h daily cycle. They were fed approximately 120 g of Purina Monkey Chow daily in the afternoon, and had drinking water available at all times. The animals were used once a week in the yawning experiments.
2.2. Procedure
During experimental sessions, the animals were placed in a plexiglas primate restraining chair (Plas Labs), which was housed in a sound-attenuating cubicle with a 60-W light in the ceiling and forced-air ventilation. A speaker in the cubicle provided masking noise. A one-way mirror window allowed video-recording of the face of the animal during the experimental session.
In the morning of an experimental day, the animal was taken from its home cage, placed in the chair, and allowed 30 min for acclimation. During this time, behavior was recorded. An i.m. injection was then given, and recording continued without interruption for an additional 40 min. For antagonism studies, the antagonist was injected at the beginning of the 30-min acclimation period.
After the experiment, the videotape was viewed, and the number of yawns and periods of time when both eyelids were closed was recorded. Yawning is distinguished from other mouth movements by full extension of the jaws, withdrawal of the lips, and exposure of teeth.
2.3. Drugs
The following drugs were used: apomorphine HCI (Sigma), quinpirole HCI (Eli Lilly and Co.), S-( - )-3(3-hydroxyphenyl)-N-( 1 -propyl)piperidine (S(- )-3PPP) HCI (Research Biochem., Inc.), (± )-SKF 38393 HCI (Research Biochem., Inc.), physostigmine salicylate (Sigma), (+ )-SCH 23390 HCI (Research Biochem., Inc.), (± )-sulpiride (Sigma), and chlorpromazine HCI (Sigma). All the compounds were dissolved in saline solution and injected i.m.
3. Results
Spontaneous yawning was evaluated by following the experimental protocol and injecting saline after the 30-min acclimation. Each of the five monkeys was studied in four different experimental sessions. The frequency of spontaneous yawns did not exceed one yawn per monkey per session. Spontaneous yawning was, therefore, an extremely rare occurrence under these experimental conditions. Likewise, there were no significant periods of eyelid closure during control sessions. The maximum response was 23 s in 30 min for one monkey.
Injections of apomorphine and quinpirole produced yawning in all five monkeys, with a significant change from saline at 0.03 and 0.01 mg/kg, respectively (table 1). The effect has a fast onset, and seldom lasted more than 20 min. (- )-3-PPP also produced yawning, but only at much higher doses (P <0.05 at 1 mg/kg), and did not reach the same frequency as did the other two compounds. For monkeys B53, B57 and 659, a biphasic dose-response relation is noted in (- )-3-PPP-induced yawning. SKF 38393 (3 mg/kg) produced no yawning. Pretreatment with 3 mg/kg of SKF 38393 30 min before a challenge dose of quinpirole (0.003 mg/kg) increased yawning in two of the five monkeys. Physostigmine was tested at 0.03 mg/kg with no yawning observed. A higner dose (0.1 mg/kg) of physostigmine produced excessive salivation and mouth movement, making evaluation of yawning difficult.
For each experimental session, the video recording was also examined for periods of eyelid closure as an indicator of drowsiness and sleep. The dopamine agofists, at effective doses for yawning, produced only brief periods of sleep in two to three monkeys. During 20 min of observation, the best responders had the following cumulated time of eyelid closure: apomorphine (81 s, 0.03 mg/kg, monkey 659), quinpirole (146 s, 0.03 mg/kg, monkey 57B), and (- )-3-PPP (4 s, 0.3 mg/kg, monkey B53). Yawning, therefore, was not accompanied by any significant sign of drowsiness.
Several dopamine antagonists were tested for blockade of the yawning response from apomorphine (fig. 1). Both chlorpromazine (0.1 mg/kg) and SCH 23390 (0.03 mg/kg) antagonized the yawning (P <0.05). The selective D2 antagonist, sulpiride, was ineffective at doses up to 10 mg/kg. The combination of chlorpromazine or SCH 23390 with apomorphine resulted in increased eyelid closure in some, but not all, monkeys. The addition of sulpiride to apomorphine did not increase eyelid closure.
4. Discussion
We have shown in this study that rhesus monkeys responded to dopamine agonists with increased yawning, similar to that observed in rats and humans. In contrast to rats (Zarrindast and Poursoltan, 1989), no yawning was observed in monkeys after physostigmine. The effective doses for yawning were quite low when compared to other behavioral responses from dopaminergic stimulation. For instance, we have studied the discriminative stimulus effect of apomorphine in monkeys (Tang and Code, [989). In that study, 0.01 and 0.03 mg/kg of apomorphine or 1 mg/kg of ( - )-3PPP produced no effect on the rate of lever-press for food pellets.
An absence of eyelid closure at the yawning doses indicated no sign of drowsiness. We previously used an identical procedure to observe the sedative effect of benzodiazepines by recording eyelid closure in monkeys. No yawning was seen at doses of triazolam or diazepam which produced prolonged eyelid closure.
The dopaminergic-induced yawning in monkeys, therefore, appears to be unrelated to the sedative effects observed with these compounds in humans.
(- )-3-PPP produced a significant increase in instances of yawning in rhesus monkeys, but not to the same frequency as apomorphine or quinpirole. This compound has been reported to produce a very low, statistically insignificant, occurrence of yawning in rats (Gower et at., 1984; Stable and Ungerstedt. 1984). Since (- )-3-PPP produced yawning in human subjects at i.m. doses of about 30 mg (C. Tamminga, personal communication), the monkeys appear to be a sensitive species, like humans, for this response. The relatively low frequency of response from (- )-3-PPP, however, is consistent with this compound being a dopamine partial agonist.
It is surprising that in this study the D,-selective antagonist, sulpiride, failed to block the apomorphineinduced yawning, since studies in rats reported complete blockade (e.g. Dubuc et at., 1982). It is possible that the 30-min pretreatment time was too short for this compound to reach optimal blood level. However, we did find in an earlier study that the 10 mg/kg dose of sulpiride blocked the discriminative cue effect of apomorphine (0.1 mg/kg) with a similar pretreatment protocol (Tang and Code. 1989). It is possible that the mechanism/site of the yawning response has a greater D, receptor reserve in monkeys than in rats, which requires a greater antagonist concentration for complete blockade. A higher dose of sulpiride is expected to be effective, although the poor solubility has kept us from testing such doses in this study.
The effective antagonism of SCI-I 23390 confirms a permissive role of the D1 receptor in the yawning response. This hypothesis is not necessarily inconsistent with the fact that the D1 agonist, SKF 38393, had no effect when given alone and had only a modest effect potentiating quinpirole. If a certain threshold level of D1 activation is all that is needed, additional D1 stimulation may have no greater effect. Since SKF 38393 is a partial agonist for the receptor, it may, in fact, behave as an antagonist for that receptor under certain circumstances (Zarrindast and Poursoltan, 1989). In summary, the results in this study suggest that dopaminergic-induced yawning involves both and D receptors. The relative importance of the two receptor subtypes depends on the species, with the rhesus monkey perhaps being more similar to humans than is the rat.


Gessa GL Stretchings and yawnings induced by adrenocorticotrophic hormone Nature 23/07/1966; n°5047; p426-427
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 Jan 1-15;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 Dec;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 Apr; 53(4):1017-21
Laing J, Ogilvie R EEG correlats of yawning during sleep onset Sleep Research 1988; 17; p98
Lobo LL, Neumann BG, Eidman DS, Tufik S Effects of REM sleep deprivation of ACTH-induced yawning. Pharmacology 1990;40(3):174-8
Molgilnicka E REM sleep deprivation changes behavioral response to catecholaminergic and serotoninergic receptor activation in rats Pharmacol Biochem Behav 1981; 15; 1; 149-151
Stahle L Do autoreceptors mediate dopamine agonist-induced yawning and suppression of exploration ? a critical review. Psychopharmacology 1992; 106; 1-13
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 Nov-Dec;308:32-8
Stahle L Do autoreceptors mediate dopamine agonist-induced yawning and suppression of exploration ? a critical review. Psychopharmacology 1992; 106; 1-13
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; vol 58; n 1; p 1881-18