Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior
Collins G et al




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23 janvier 2003
1992; 106; 1-13
Do autoreceptors mediate dopamine agonist-induced yawning and suppression of exploration ? a critical review
Stahle Lars
Department of pharmacology, Karolinska Institute Sockholm, Sweden


Dopamine (DA) synthesis is generally assumed to bc controlled by end-product inhibition and is autoreceptors. Similarly, DA release and the firing of DA neurons are also modulated by the degree of stimulation of DA autoreceptors. There is, however, some controversy as to whether or not all brain regions possess autoreceptors.

It has repeatedly been observed that signs of DA autoreceptor stimulation in vivo are seen with relativ y small doses of DA agonists. High doses of DA agonists induce stereotyped sequences in rodents, e.g. locomotion, sniffing and gnawing behaviour in rats, while small doses of, for example, apomorphine (APO) cause a suppression of normal activity of rats and mice and induces episodes of yawning behaviour.

The fact that neurochemical and electrophysiological signs of DA autoreceptor stimulation can be induced in approximately the same dose range by DA agonists as the doses required to induce yawning and suppression of exploration has been interpreted as a causal connection. Thus, it bas been hypothesized that yawning and suppression of exploration induced by DA agonists are mediated by a reduction of synaptic levels of DA which, in turn, is mediated by stimulation of autoreceptors. In the following this hypothesis is referred to as "the autoreceptor hypothesis", a simplified illustration of which is given in Fig.

Recently, considerable efforts have been made to find drugs that are selective agonists on DA autoreceptors which have been motivated by reports on clinical effects of low doses of APO, or other DA agonists, on schizophrenia and hyperkinetic disorders. Induction of yawning and, in particular, suppression of exploration have been used extensively for screening purposes. However, the autoreceptor hypothesis (vide supra) lias recently been questioned by several research groups. The aim of this review is to critically examine the hypothesis that DA autoreceptor stimulation mediate yawning and suppression of exploration. The work performed in our laboratory will be reviewed and discussed in considerable detail and their relation to findings in other groups will be discussed. The autoreceptor hypoth esis has the advantage that it leads to many predictions that can be tested: the predictions investigated here were:

1 . reduction of synaptic DA to a given level by mechanisms other than autoreceptor stimulation should yield behavioural effects similar to those induced by DA agonists

2. increased release of DA should abolish autoreceptor mediated responses

3. there should be a temporal correlation between behavioural effects and effects on synaptic DA levels after autoreceptor stimulation

4. reduction of synaptic DA levels should result in a potentiation of autoreceptor-mediated responses, or the autoreceptor-mediated response should be abolislied, if the levels are too low. [...]

Discussion : we will firt discuss the data underlying the autoreptor hypothesis and then continue with the present results, alternative interpretations and the clinical perspective.

Data underlying the autoreceptor hypothesis : The original finding, which led to the formulation of the autoreceptor hypothesis (as defined in the introduction), was that APO inhibits tyrosine hydroxylation (dopa accumulation in NSD 1015 - treated mice) in the same doses as motor activity of mice is suppressed. This result has been confirmed beyond doubt by many investigators. An extension of this evidence is provided by Brown, who showed that inhibition of tyrosine hydroxylation (dopa accumulation in GBL- and NSD 1015-treated rats) by a wide range of DA agonists correlate nicely with suppression of exploration in mice. However, it is uncertain to what extent the NSD method reflects changes in synaptic levels of DA. Thus, Brown found that alphaMPT (250 mg/kg, 1 h) did not alter the behavioural effects of DA agonists which is compatible with our findings. Their result was interpreted as evidence that DA agonists suppress exploration by a mechanism independent of inhibition of synthesis. This certainly agrees with our finding that doses of alphaMPT (50-100 mg/kg) which reduce extracellular DA more than a behaviourally active dose of APO (0.05 nig/kg) have no effect on behaviour. Thus, we conclude that inhibition of synthesis is not the mechanism by which DA agonists suppress exploration or induce yawning. These findings demonstrate that the evidence used to formulate the autoreceptor hypothesis in the first place is indirect and relies upon the assumption that changes in synthesis are followed by similar changes in release.

Other results supporting the autoreceptor hypothesis are that lesions of the striatum or the substantia nigra by 6-OH DA or in the substantia nigra by electrocoagulation abolish yawning induced by APO given systemically. However, Scheel-Krüger found that yawning, induced by local injection of DA agonists into the striatum, was not abolislied by 6-OHDA lesions in the same region. Recently Melis reported that APO injected locally into the hypothalamus elicit yawning in very low doses (5 ng). Hence, it cannot be excluded that this discrepancy is due to non-specific effects of the larger lesions. It should be noted that neither lesion was reported to induce yawning, as may be expected since both autoreceptor stimulation and 6-OHDA lesions should result in a reduced DA transmission.

It has also been suggested that the antagonistic effect of reserpine (4 h) on APO-induced yawning supports the autoreceptor hypothesis. Surprisingly, the finding that reserpine (18 h) potentiates yawning induced by APO was also regarded as evidence in favour of the autoreceptor hypothesis. Serra et al. found that reserpine (18 h) alone induces yawning in an alphaMPT- and sulpiride-sensitive manner, which was regarded as evidence against the autoreceptor hypothesis. Hence, the effects of reserpine on APO-induced yawning are not unimpeachable evidence in favour of the hypothesis.

Data questioning the autoreceptor hypothesis : Behavioural evidence that low doses of DA agonists have effects similar to postsynaptic DA receptor stimulation is provided by the fact that suppression of exploration and induction of stereotypies are not two extremes on the same scale. The use of a method where several beliavioural variables can be recorded simultaneously is a prerequisite for this observation. It is well known that recording of some variables can give seriously misleading results when comparisons between different devices are attempted. By combining the multivariate registration with multivariate statistical analysis one ensures that, given the limitations of the recording devices, changes in behavioural patterns are detected. Thus, we conclude that an "activity-inactivity" scale does not account for the dose-response to DA agonists.

Compounds that are D2 receptor agonists or mixed D1/D2 agonists suppress exploration in various models. The D1 partial agonist SKF 38393 has also been found to suppress exploration, although this finding is controversial. We found that SKF 38393-induced suppression of exploration was not antagonised by sulpiride. Thus, we conclude that suppression of exploration is D2 receptor mediated.

In addition, we have found that suppression of exploration can only be antagonised by D2-receptor blocking agents. The selective D1 antagonists SCH 23390 has no effect on APO-induced suppression of exploration. In contrast, the selectiveD2 receptor antagonist sulpiride completely antagonises this response in a wide dose range. The antagonistic effects by other DA receptor blockers, e.g. haloperidol and cis-flupenthixol are more controversial.

Some authors report antagonistic properties of haloperidol while others find no effect. Similarily, cis-flupenthixol has beenreported to be eiher antagonistic or to have no effect. Taken together, many neuroleptics can, in a small dose range, antagonize suppression of exploration induced by DA agonists in some models in some species. Two D2 antagonists stand out as unique. Remoxipride has no antagonistic effect on APO-induced suppression of exploration and sulpiride is the only substance that is an effective antagonist over a wide dose range (Stàhle and Ungerstedt 1986b, 1987b). In addition, the antagonisrn by sulpiride is surmontable. We have also found that extracellular levels of sulpiride in the dose range corresponding to the in vivo Kd of 5-10 mg/kg does not exceed 10 nM. These data suggest that, e.g. haloperidol- and remoxipride-induced suppression of exploration is mediated by a different population of D2 receptors than sulpiride. Thus, it is concluded that DA agonist-induced suppression of exploration is mediated by a subclass of D2-receptor.

An interesting observation is that haloperidol and sulpiride both cause an increase in extracellular DA, DOPAC and HVA and levels of DOPAC and HVA are increased by remoxipride. From this it may be concluded that the receptors mediating increases in extracellular DA, DOPAC and HVA are pharmacologically distinct from those mediating suppression of exploration.

These observations, together with our early finding that there was discrepancy in the time-course of the action of APO on extracellular DA and suppression of exploration prompted us to test the autoreceptor hypothesis. In particular, the four predictions listed in the introduction were investigated by combined microdialysis and behavioural studies. Our conclusions based on the results obtained from these tests are:

1. Reduction of extracellular DA to a given level by drugs with different pharmacological mode of action does not result in similar behavioural changes. Inhibition of tyrosine hydroxylase by MPT reduced extracellular levels of DA in microdialysis experiments. The effects of MPT (50-100 mg/kg) were of at least the same magnitude as the effects of APO (0.05 mg/kg). However, these doses of MPT had no effect on exploration and did not induce yawning. Reserpine (2 mg/kg) reduced DA levels to approximately the same extent as APO (0.05 mg/kg). However, 3 h after injection of reserpine there were no behavioural effects of the drug while after 4 h there was a strong suppression of exploration. Similar comparisons hold for pergolide and EMD 23448.

2. An increase in extracellular DA could not abolish the DA agonist induced yawning and suppression of exploration. Thus, amphetamine (0.2 mg/kg) pretreatment did not abolish the behavioural effects of APO or pergolide in spite of the fact that this dose of amphetamine elevated extracellular DA when given in conjunction with pergolide.

3. There was a poor correlation in time between the effects of APO (0.05 mg/kg), pergolide (0.02 mg/kg), EMD 23448 (2 mg/kg), ocMPT (200 mg/kg) or reserpine (2 mg/kg) on behaviour and reduction of DA levels. APO-induced yawning and suppression of exploration and pergolide- and EMD 23448-induced yawning had a shorter latency than the reduction of DA levels. The opposite relation was observed for aMPT- or reserpineinduced suppression of exploration.

4. Combined treatment with aMPT and APO, but not pergolide, caused a more pronounced suppression of exploration than did APO and pergolide alone. The dose-response curve for APO-induced yawning was not shifted by MPT (200 mg/kg) pretreatment.

Thus, the majority of the predictions made by the autoreceptor hypothesis did not hold. The only two findings supporting the autoreceptor hypothesis are that reserpine suppressed exploration and that the suppressive effect of MPT on exploration added to that of APO (however, not to that of pergolide).

It may be argued that the brain regions investigated by microdialysis are not those mediating yawning and suppression of exploration. In fact, there is a considerable amount of data supporting the hypothesis that suppression of exploration by DA agonists can be elicited from the accumbens. Given that these findings can be taken as evidence that suppression of exploration induced by systemically administered

APO is also mediated by DA receptor stimulation in the accumbens it would seem more relevant to study the effects of APO and aMPT in this region. We have found that the effect of APO (0.05 mg/kg) on extracellular DA is smaller in the accumbens (reduction to 80%) compared to the striatum while the effect of ocMPT (50 mg/kg causes reduction to 40%) is more similar to the effect in the striatum.

DA agonist-induced yawning is probably elicited from inside the blood-brain barrier. However, local injections of DA agonists have been found to elicit yawning in several locations in the brain such as the striatum, the septum, the central amygdaloid nucleus and the hypothalamus. Lesion experiments have suggested that the striatum is critically involved. Thus, no definite conclusion can be drawn with respect to the site (-s?) in the brain responsible for mediating DA agonist-induced yawning. However, the finding that combined treatment with amphetamine and SCH 23390 induces yawning is a very strong argument against autoreceptor mediation, since it appears impossible that post-synaptic D2-receptor stimulation can be reduced by this treatment.

Thus, it is concluded that neither the primary evidence in the literature, nor the present findings constitute convincing evidence in favour of the autoreceptor hypothesis. In most cases, predictions made from the hypothesis do not hold when tested. An alternative hypothesis is that postsynaptic receptors mediate yawning and suppression of exploration. Another hypothesis for the mode of action of DA agonists on behaviour must therefore be proposed. The obvious alternative is that populations of sensitive postsynaptic receptors mediate DA agonistinduced yawning and suppression of exploration. There is, however, little direct evidence in favour of this hypothesis. The most direct evidence is that amphetamine plus SCH23390 induces yawning in a dose where amphetamine given alone induces strong stereotypies and causes an approximately 10-fold increase of the extracellular levels of DA. The postsynaptic receptor hypothesis is based partly on the assumption that there is a variation in the sensitivity of DA receptors between brain regions. The fact that behavioural and electrophysiological effects of DA agonists can be observed in different dose ranges directly supports the validity of this assumption. An important factor contributing to the understanding of the variation in sensitivity of different receptor populations is the possibility of a difference in receptor reserve between brain regions, between postsynaptic receptors and autoreceptors etc.

An important question is whether yawning and suppression of exploration are equivalent or not. Evidence that yawning and suppression of exploration are pharmacologically distinct is provided by the finding that scopolamine does not antagonise suppression of exploration while yawning is blocked by anticholinergics. Furthermore, remoxipride inhibits APO induced yawning but not suppression of exploration. Thus, we conclude that yawning and suppression of exploration are functionally distinct.

Clinical implications

One of the motives behind the massive amount of research around the effects of low doses of DA agonists is a number of reports that DA-agonists are effective in various psychiatric conditions such as schizophrenia and Gille delaTourette's disease as well as neurological disorders such as Huntington's chorea, tardive dyskinesia and torticollis. Later reports have been less optimistic, showing that the effects on schizophrenia are shortlived and prone to desensitization. The clinical efficacy of DA agonists is a problem whose understanding depends to some extent on the understanding of behavioural models. ln view of the present data, it is possible that the clinical effects of DA agonists are not mediated by stimulation of DA autoreceptors. In fact, it has been suggested that the low dose effects of APO, because they are selectively antagonised by sulpiride, may serve as a model for negative symptoms of schizophrenia. We note that the theoretical understanding of the effects of DA agonists in clinical states and animal models is a completely different problem from the demonstration of true clinical efficacy.


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, Ungerstedt U Discrepancy in the time course of EMD 23448 induced yawning and reduction of extracellular dopamine Psychopharmacology 1989; 97; 275-276
-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 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
-Stahle L, Ungerstedt U Yawning and suppression of exploration in amphetamine-treated rats, incompatibility with the autoreceptor hypothesis Psychopharmacology 1989; 97; 553-560
-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
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