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mise à jour du
17 juin 2004
Pharmacol Biochem Behav
1990; 35; 201-209
lexique
Yawning and suppresssion of exploration
induced by dopamine agonists:
no relation to extracellular strital levels of dopamine
Stahle L, Ungerstedt U
Department of pharmacology, Karolinska Institute. Sockholm, Sweden

Chat-logomini

Dopamine (DA) autoreceptors are believed to autoregulate the activity of DA neurons by inhibiting release of DA, inhibiting tyrosine hydroxylase, decreasing DA utilisation and reducing the fuing of DA neurons. The autoreceptors are assumed to be more sensitive to treatment with DA agonists than the postsynaptic receptors. It bas also been hypothesised that behavioural effects induced by low doses of DA agonists are mediated by stimulation of DA autoreceptors. Thus, the behavioural effects of DA agonists such as yawning and motor inhibition have been used to screen for autoreceptor active substances. However, it bas been suggested that DA agonist-induced yawning, sedation and suppression of exploratory behaviour are not mediated by stimulation of DA autoreceptors.
 
The present study was undertaken to further investigate the hypothesis that the behavioural effects of low doses of DA agonists are mediated by a reduction of the extracellular levels of DA (from hereon referred to as the autoreceptor hypothesis). This was done by comparing the effects on extracellular levels of DA of apomorphine (APO), the tyrosine hydroxylase inhibitor a-methyldl-p-tyrosine (a-MPT) and the monoamine storage blocker reserpine. Microalysis was used to sample the extracellular DA. The results from the microalysis experiments were then compared to behavioural effects of the drugs. The findings suggest that the behavioural effects of low doses of DA agonists are not correlated to the extracellular levels of DA. Preliminary accounts of the present work have been published elsewhere. [...]
 
Discussion : The idea that low doses of DA agonists selectively stimulate DA autoreceptors was originally put forward by Carlsson and Strömborn and also by Ljungberg and Ungerstedt and DiChiara et al. The hypothesis is based on the finding that low doses of DA agonists inhibit tyrosine hydroxylase without inducing stereotyped behaviour which has been subsequently substantiated. The fact that APO in the low-dose range also suppresses exploration, and that the effects of a wide range of DA agonists on behaviour and synthesis are strongly correlated, suggested that suppression of exploration also is mediated by DA autorecepters. Similar arguments were used to formulate the same hypothesis for yawning behaviour.
 
Other evidence supporting the autoreceptor hypothesis bas been put forward. Yawning behaviour can be suppressed by pretreatment (4 bouts) with reserpine. This was interpreted as a maximal reduction of synaptic DA to which the effect of APO could not be added. Surprisingly, Yamada and Furukawa found that reserpine (24 bouts pretreatment time) enhanced yawning which they interpreted as an additive effect of APO and reserpine. In both cases the findings were taken as evidence in favour of the autoreceptor hypothesis. Serra et al. reported that reserpine alone induces yawning at 24-hr pretreatment, but not at 4 hr which they interpreted as an argument against the autoreceptor hypothesis.
 
Dourish and Hutson found that 6-OHDA lesions of striatal DA terminals abolish yawning behaviour induced by APO 0. 1 mg/kg. The authors interpreted their findings as due to a loss of autoreceptors. Similarly, recent observations by Stoessel et al. show that even smaller doses of APO did not induce yawning in rats with 6-OHDA-induced substantia nigra lesions as would have been expected if postsynaptic receptors had mediated the response. However, intrastriatal injections of DA agonists elicit yawning in rats with local 6-OHDA lesions at the injection site. Hence, it cannot be excluded that the results of Dourish and Hutson and Stoessel et al. are caused by nonspecific blockade of the expression of yawning, e.g., through behavioural competition. Recently, Melis et al. suggested that yawning is mediated by hypothalamic DA.
 
The present study was undertaken to further test the hypothesis that suppression of exploration and induction of yawning by low doses of DA agonists are mediated by stimulation of DA autoreceptors. From the autoreceptor hypothesis a number of predictions follow. In the present study three such predictions were tested:
 
1 . The relation between the synaptic levels of DA and behaviour should be the same if DA levels are reduced by an agonist or by some other drug, e.g., a-MPT (a tyrosine hydroxylase inhibitor) or reserpine (a monoamine storage blocker).
 
2. The reduction of synaptic levels of DA and the behavioural effects of DA agonists should have a similar time-course.
 
3. The dose-response curve for the behavioural effects of a DA agonist should be shifted to the left (i.e, the response should be enhanced) by pretreatment with a-MPT.
 
Effects of APo, a-MPT or reserpine on behaviour and extracellular dopamine levels
It was expected, from the autoreceptor hypothesis, that when the extracellular levels of DA are reduced to a given level by APO, reserpine or a-MPT, the behavioural effects should be similar. The results from the present study show that a-MPT (50 and 100 mg/kg), reserpine (2 mg/kg) and APO (0.05 mgfkg) all reduce the extracellular levels of DA to between 40% and 60% of basal levels. However, a-MPT (50 and 100 mg/kg) did not suppress exploration. Reserpine (2 mg/kg) had no effect on behaviour after 3 hr, but suppressed exploration after 4 hr. APO (0.05 mg/kg) suppressed exploratory behaviour. Pergolide (0.005 mg/kg), which has previously been shown to suppress exploration (48), had no effect on extracellular levels of DA in the striatum. Thus, it was not possible to demonstrate the presence of a relation between reduced extracellular levels of DA and suppression of exploratory behaviour.
 
The fact that reserpine (2 mg/kg) did affect behaviour 4 hr after administration may be taken as evidence supporting the autoreceptor hypothesis with respect to suppression of exploration, though not for yawning because no yawning was induced by reserpine. It is, however, not easy to explain why there is a drastic change in behaviour between 3 and 4 hr after injection, while there is only a small decline in extracellular DA levels. A possible explanation is that the effect of reserpine is uneven and that, in some critical synapses, there is a large loss at 3-4 hr after injection. Another possibility is that reduced noradrenaline neurotransmission contributes to the suppressive effect on exploration by reserpine.
 
In the case of yawning behaviour, the discrepancy between the effects on behaviour and neurochemistry of DA agonists and a-MPT and reserpine is even more obvious since neither a-MPT nor reserpine can induce yawning behaviour within the first 5 hr postinjection. In addition, it has been reported that no DA antagonist induces yawning behaviour and the same result bas been obtained in this laboratory for SCH 23390 and raclopride. In this connection it is noteworthy that both yawning and suppression of exploration can be elicited by dopamine agonists in the presence of amphetamine and that neuroleptic drugs can elicit yawning in rats treated with high doses of dopamine agonists or amphetamine.
 
The dialysis experiments in the present study were performed in the striatum. We have recently found that the effects of APO on DA levels are smaller in the accumbens and the frontal cortex than in the striatum, while alphaMPT has approximately the same effect in the acumbens and the striatum. Hence, a regional variation in the sensitivity to APO is not likely to account for the present findings. This is important since it has been suggested that suppression of exploration is mediated by the nucleus accumbens.
 
Time-Response to APO, Pergolide and otMPT on Behaviour and Extracellular Dopamine Levels
 
The time-course for suppression of exploration and induction of yawning by APO (0.05 µg) were found to have a more rapid onset and a shorter duration than the effect on extracelluIar DA levels A similar discrepancy in the time-course for yawning and changes in DA levels was obtained with pergolide (0.02 mg/kg) and with EMD 23448 and BHT 920. The time-course for the effects of APO on exploration are consistent with findings in mice. Interestingly, it has been shown that the levels of APO in the rat brain follow a time-course similar to that of the behavioural effects. Thus, there is no direct relation in time between behavioural effects induced by DA agonists and the reduction of DA levels.
 
In a previously published article, we tentatively explained this discrepancy in time-course between behavioural and neurochemical effects as due to rapid changes in autoreceptor sensitivity. However, such a mechanism does not seem to explain the present findings because we have found that the yawning induced by repeated APO administration shows only slight desensitisation and suppression of exploration shows no desensitisation. Neither is it likely that changes in DA levels measured by means of microdialysis are delayed because of slow diffusion of DA into the probe. This conclusion is supported by the present finding that the suppression of exploration following a-MPT had a slower onset than the decrease of DA levels, ie., the opposite to the findings with APO. Thus, it is concluded that the observed discrepancy in time-course between changes in behaviour and changes in the extracellular levels of DA reflects a true discrepancy in time.
 
Effects of a-MPT, on APO-Induced Yawning and Suppression of Exploration
 
Pretreatment with a-MPT did not shift the dose-response curve for APO-induced yawning (Fig. 4). The effect of aMPT on suppression of exploration added to that of APO, but not to pergolide. It was predicted that the yawning dose-response curve would be shifted to the left and that a-MPT per se would induce yawning. Thus, it seems likely that induction of yawning by DA agonists is independent of the extracellular level of DA. The same conclusion was drawn by Scheel-Krüger on the basis of 6-OHDA lesions in dorsal striatum and local injections of DA agonists in the lesioned area. The reason why die effect of a-MPT on suppression of exploration adds to that of APO, but not pergolide is not clear.
 
In conclusion, the present study shows that behavioural effects of low doses of DA agonists are not related to a reduction of the extracellular levels of DA. If the extracellular levels of DA reflect the synaptic levels of DA, this may be interpreted as evidence against the autoreceptor hypothesis. It cannot be excluded that autoreceptor mediated effects of a different nature, such as changes in release of co-transmitters or changes in firing pattern, account for the behavioural effects of low doses of DA agonists. However, we would like to propose that these behavioural effects are mediated by a population of postsynaptic DA receptors being more sensitive to DA agonists than other postsynaptic receptor populations such as the recepters that mediate stereotyped behaviour following APO. Several explanations for the high receptor sensitivity are possible such as a large amount of spare receptors or that the receptor is pharmacologically different from other DA receptors. This hypothesis has the advantage that it is reasonably simple to test.
 
-Lynch MR Dissociation of autoreceptor activation and behavioral consequences of low doses apomorphine treatment Prog Neuro-Psychopharmacol & Biol Psychiat 1991; 15; 689-698
-Morelli M et al Antagonism of apomorphine-induced yawning by SCH 23390: Evidence against the autoreceptor hypothesis Psychopharmacology 1986; 89; 259-260
-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