lkopean Journal ojJ%amacolugy, 201(1991) 235-238 6 1991 Elsevier Science Publishers B.V. All rights reserved 0014-2999/91/$03,50 ADONIS 0014299991005908

235

EJP 20894

Short communkat:ation

Yawning produced by dopa~ine agonists in rhesus monkeys Robert A. Code and Andrew H. Tang

Received 4 April 1991,revised MS received 17 June 1991,accepted 2 July 1991

Yawning was recorded from five rhesus monkeys restrained in a chair after i.m. injection of dopaminergic compounds: a~morphine (0.03 mgfkg), quinpirol~(0.01mg/k~), and ( - ~3~3-hydro~henyl)-~-~l-propyi~ipe~din~ (1 mg/kgf. 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 com~unds is discussed. Yawning; Dopaminergic

compounds; (Rhesus monkey)

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 (Stable 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 D,-selective partial agonist, SKF 38393, produces no yawning when given alone. But, both antagonism (Zarrindast and P~ursoltan, 1989;) and potentiation (Spina et al., 1989) by SKF 38393 on dopaminergic yawning in rats have been reported. Likewise, antagonism of dopaminergic-induced yawning in rats by SCH 23390, a selective D, antagonist, was found by some investigators (Morelli et al., 19861, but not others (Zarrindast and Pou~oltan, 1989).Mixed

Correspondence to A.H. Tang. CNS Diseases Research ZSI-W-4. The Upjohn Company, 301 Henriettu Street. Kalamazoo, MI 49001. USA. Tel. i.~l~,3~.7~94. fax l.~l~.38S,4S2~.

dopamine D,/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 (Lal, 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. Aniimls 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-l&O0 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. Procedm? 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-recordiKg 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-c -J-3(S( - J-3(3-hydroxyphenyl)-N-t 1-propyl)piperidine PPP) HCI (Research Biochem., Inc.), (+ )-SKF 38393 HCI (Research Biochem., Inc.), physostigmine salicylate (Sigma), ( + )-SCH 23390 HCI (Research Biochem., Inc.), ( + I-sulpiride (Sigma), and chlorpromazine HCI (Sigma). All the compounds were dissolved in saline solution and injected i.m.

3. Results SPontatXOtts yawning was evaluated by following the experimental protocol and injecting saline after the

TABLE

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 ( - l-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 higher 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 agonists, 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 6591, quinpirole (146 s, 0.03 mg/kg, monkey 57B), and (-)-3-PPP (4 s, 0.3

1

Number of yawning produced in five rhesus monkeys during the first 20 min after i.m. injection of drugs. Drug

Dose

Monkeys

mg/kg

B53

B54

B57

c51

0

1

0

0

0

0

Saline

659

Median (N=S)

Apomorphine

0.01 0.03

10 3

2 1X

8 10

3 15

2 6

3 10h

Quinpirole

0.003 0.01

3 I!

0 6

0 9

7 14

0 1

0 9h

(- I-3-PPP

0.3

x

0

1

1

IO

0

3

4

9

0 6 0

1 6” 3

3

3 7 0

SKF-38393

3

0

0

0

0

0

0

Physostigmine

0.03

0

1

0

(1

0

Q

SKF-3X393

3 x

II

3

7

1

3”

I

+ quinpirole

O.Of~3

” P < 0.05: h P < 0.01: Wilcoxora’s rank sum test comparing to saline treatment.

237

Monkeys:

. --CPZ--

--SCH--

--Sulpiride--

Fig. I. Antagonism of yawning produced by apomorphine (0.03 mg/kg i.m.) in five rhesus monkeys.The number of yawns during the first 20 min after the injection of apomorphine was scored from a videotape recording. The antagonists were injected 30 min before the apomorphine injection. The group difference from chlorpromazine (0.1 mg/kg) or SCH 23390 (0.03 mg/kg) and apomorphine alone is significant (P < 0.05. Wilcoxon’s rank sum test).

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 D, 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 resporided 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, 1989). In that study, 0.01 and 0.03 mg/kg of apomorphine or 1 mg/kg of ( - J-3. PPP 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., 19821. 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 SCH 23390 confirms a permissive role of the D, receptor in the yawning response, This hypothesis is not necessarily inconsis-

2.38

tent with the fact that the D, agonist, SKF 38393, had no effect when given alone and had only a modest effect potentiating quinpirole. If a certain threshold level of D, activation is all that is needed, additional D, stimulation may have no greater effect. Since SKF 38393 is a partial agonist for the D, receptor, it may, in fact, behave as an antagonist for that receptor under certain circtimstances (Zarrindast and Poursoltan, 1989). In summary, the results in this study suggest that dopaminergic-induced yawning involves both D, and DZ 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.

Acknowledgement We thank Mrs. D. Sutrer for her helpful suggestionsin preparing the manuscript.

References Dubuc. I.. P. Protais. 0. Colboc and .I. Costentin. 1982, Antagonism of the apomorphine-induced yawning by ‘atypical’ neuroleptics, Neuropharmacology 21. 1233.

Gower, A.J., H.H.G. Berendsen, M.M. Princen and C.L.E. Broekkamp, 1984, The yawning-penile erection syndrome as a model for putative dopamine autoreceptor activity, Eur. J. Pharmacol. 103. 81. Lal. S., 1988, Apomorphine in the evaluation of dopaminergic function in man, Prog. Neuro-Psychopharmacol. Biol. Psychiat. 12, 117. Morelli, M.. R. Longoni, L. Spina and G. Di Chiara, 1986, Antagonism of apomorphine-induced yawning by SCH 23390: evidence against the autoreceptor hypothesis, Psychopharmacology 89,259. Spina, L., R. Longoni, A. Mulas and G. Di Chiara, 1989, SKF 38393 potentiates yawning induced by LY 171555: further evidence against the autoreceptor hypothesis of yawning, Psychophhrmacology 98, 567. Stahle, L. and U. Ungerstedt. 1984, Assessment of dopamine autoreceptor agonist properties of apomorphine, (+ )-3-PPP and (- )-3PPP by recording of yawning behavior in rats, Eur. J. Pharmacol. 98. 307. Stahle. L. and U. Ungerstedt, 1990, Yawning and suppression of exploration induced by dopamine agonists: No relation to extracellular striatal levels of dopamine, Pharmacol. Biochem. Behav. 35, 201. Tang, A.H. and R.A. Code, 1989, Studies on the discriminative stimulus properties of apomorphine in rhesus monkeys, Psychopharmacology 97,418. arrindast, M.R. and M. Fnursoltan, 1989, Interaction of drugs on central dopamine recrptrlrs and cholinoceptors on yawning responses in the rat induced by apomorphine, bromocriptine or physostigmine, Br. J. Pharmacol. 96, 843.

Yawning produced by dopamine agonists in rhesus monkeys.

Yawning was recorded from five rhesus monkeys restrained in a chair after i.m. injection of dopaminergic compounds: apomorphine (0.03 mg/kg), quinpiro...
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