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19 mai 2005
1989; 97; 553-560
Yawning and suppression of exploration in amphetamine-treated rats, incompatibility with the autoreceptor hypothesis
Stahle L, Ungerstedt U
Department of Pharmacology, Karolinska Institute, Stockholm, Sweden


Low doses of dopamine agonists have been reported to reduce schizophrenic morbidity and symptoms of hyperkinetic disorders. In view of these clinical findings, it is important to establish experimental models for effects of low doses of dopamine agonists and to elucidate the underlying pharmacological mechanisms. The two behavioural models most commonly used for studying the effects of low doses of dopamine agonists are suppression of exploration in rats and mice and induction of yawning behaviour in rats. The presently most widely accepted hypothesis to explain the mechanism underlying these responses is the autoreceptor hypothesis.
According to the autoreceptor hypothesis, low doses of dopamine agonists cause behavioural changes by reducing the synaptic levels of dopamine via selective stimulation of dopamine autoreceptors. Various effects of dopamine autoreceptor stimulation may contribute to the reduced synaptic levels of dopamine such as decreased dopamine synthesis, decreased dopamine release and inhibition of the electrical activity of dopamine neurons.
The dopamine agonists do not, in the low dose range, elicit the classical signs of post-synaptic dopamine receptor stimulation, such as stereotyped behaviour and electrophysiological changes in striatal neurons.
Recently, the autoreceptor hypothesis has been questioned by several research groups. Their conclusions were based on experiments using reserpine or x-methyl-p-tyrosine to reduce the synaptic levels of dopamine, which they found did not affect the yawning response.
The present study was undertaken to further test the autoreceptor hypothesis by using amphetamine to increase the extracellular levels of dopamine and to test if both yawning and suppression of exploration could be elicited in this situation. We found that yawning, as well as suppression of exploration, can be elicited by dopamine agonists in rats treated with amphetamine in doses that are shown to increase the extracellular levels of dopamine. [...]
The aim of the present study was to test the hypothesis that both the yawning and the suppression of exploration induced by dopamine agonists are caused by a reduction of synaptic dopamine levels due to stimulation of dopamine autoreceptors. From this hypothesis, it may be predicted that if the synaptic levels of dopamine are increased above baseline then it should not be possible to elicit either yawning or suppression of exploratory behaviour.
In the present study we have used an approach opposite to that of previous studies. Instead of reducing the basal levels of dopamine by reserpine or x-methyl-p-tyrosine we increased the basal levels by amphetamine. Thus, we found that pretreatment with amphetamine (0.2 mg/kg) completely counteracted the decrease in extracellular dopamine levels induced by pergolide (0.02 mg/kg) and increased the extracellular levels of dopamine to 300% of baseline. This small dose of amphetamine was also sufficiently large to induce a slight behavioural activation, suggesting that this dose cause a stimulation of postsynaptic dopamine receptors.
Yawning behaviour induced by pergolide was not significantly antagonised by amphetamine (0.2 mg/kg) pretreatment. However, amphetamine (0.2 mg/kg) did antagonise the yawning induced by APO (0.05 mg/kg) although by no more than 30%. Thus, in spite of the fact that the levels of extracellular dopamine were increased above baseline it was possible to elicit yawning. These findings strongly suggest that dopamine agonist-induced yawning is not due to a decrease in the extracellular levels of dopamine.
Further evidence against a direct relationship between the induction of yawning and reduction of extracellular dopamine levels is that pergolide (0.02 mg/kg)-induced yawning was most intense 20-30 min after injection while the dopamine levels were lowest after between 80 and 100 min. This discrepancy in time has also been found for APO- and EMD 23448-induced behavioural effects and dopamine levels which was interpreted as evidence against a connection between dopamine levels and behaviour as discussed in detail elsewhere.
Suppression of exploration induced by APO or pergolide could not be counteracted by amphetamine pretreatment. Two different pretreatment times for amphetamine against pergolide were used in order to test exploration at the peak level of dopamine (20 mm) or at the time point when the behavioural effects of amphetamine should be at the maximum (30 mm) according to Sharp et al. (1987). These results are similar to those on yawning behaviour, in the sense that it was possible to elicit the characteristic effects of low doses of dopamine agonists in spite of the fact that the extracellular level of dopamine was increased above baseline. In case autoreceptors were involved in this response, amphetamine would have been expected to counteract the APO- or pergolide-induced suppression of exploration. We therefore conclude that dopamine agonist-induced suppression of exploration is not related to reduced extracellular levels of dopamine.
Since our results are in apparent conflict with the idea that low doses of dopamine agonists induce behavioural changes by reducing the synaptic levels of dopamine, some other explanation must be sought. Although we cannot exclude that dopamine agonists alter the release of a co-transmitter to dopamine (e.g., cholecystokinin), we would like to put forward a more easily testable hypothesis. We suggest that yawning and suppression of exploration are mediated by stimulation of populations of postsynaptic dopamine receptors. These receptors are probably of the D-2 type because of the ability of sulpiride to antagonise both responses. The fact that the apparent sensitivity of these receptors is considerably higher than the sensitivity of the receptors mediating for example stereotyped behaviour can easily be fitted into the framework of Stephenson's receptor, theory (1956), which allows for a receptor reserve. The existence of a considerable receptor reserve (spare receptors) in the receptor population controlling dopamine synthesis has recently been demonstrated. We suggest that this is also the case for the receptor populations mediating yawning and suppression of exploration. An equivalent suggestion is that the fraction (percentage) of spare (dopamine) receptors is larger in the brain structures mediating suppression of exploration and yawning than those mediating induction of locomotion and stereotyped behaviour.
Our hypothesis is further supported by the finding that a large dose of amphetamine (2 mg/kg), in combination with the D-1 receptor antagonist SCH 23390 (0.05 mg/kg) induced yawning. This dose of amphetamine increases the extracellular dopamine levels approximately 10 times above baseline and it induces strong stereotyped behaviour. The yawning behaviour elicited by combined amphetamine plus SCH 23390 treatment was not as intense as that induced by APO or pergolide alone. Instead, the intensity of yawning was comparable with that following combined treatment with APO and SCH 23390 which causes a 50% reduction in the APO-induced yawning. The fact that yawning did not appear unless amphetamine was combined with SCH 23390 may be explained as due to behavioural competition, i.e., that the amphetamine-induced stereotyped behaviour obscures yawning. Stereotypies induced by dopamine agonists and amphetamine are readily antagonised by SCH 23390 , suggesting a functional interaction between D-1 and D-2 receptors. The present findings indicate that a similar but less pronounced interaction takes place in the mediation of dopamine agonist induced yawning, as suggested by Lognoni et al. (1987). Hence, SCH 23390 may uncover stimulation of yawning mediating dopamine receptors by dopamine released through the action of amphetamine. A similar effect has been described for APO given in a high dose combined with various neuroleptics.
The use of conscious rats with microdialysis probe guides implanted made it possible to simultaneously monitor yawning behaviour and changes in the extracellular levels of dopamine, DOPAC, HVA and 5HIAA. However, the extent to which extracellular levels of dopamine, as sampled by microdialysis, actually reflect the levels of dopamine in the synapses is not known. Unfortunately, there is no method available to investigate this problem and we are therefore forced to make the assumption that the level of dopamine in the dialysate is a function of, among other factors, the synaptic level of dopamine. Similarly, it may be questioned whether or not the doses of amphetamine used in the present study act in such a way that they really overcome the decrease in dopamine release following treatment with APO. It may be that APO reduces the amount released per nerve impulse while amphetamine increases the synaptic levels between release events in the synapse. Integrated over time the synaptic levels may appear increased, but this would not be the case during the transmission process. Again, we have no way to test this possibility and we are consequently forced to work under the assumption that the transmission process in reality is enhanced by amphetamine + APO compared to baseline transmission.
In summary, in view of our findings that dopamine agofists can induce yawning behaviour and suppress exploratory behaviour when dopamine neurotransmission is apparently enhanced, we suggest that these behaviours are not the consequence of autoreceptor stimulation, but that they are mediated through a stimulatory action on postsynaptic dopamine receptors.
-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