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17 juin 2004
Europ J Pharmacol
1984; 98; 307-310
Assessment of dopamine autoreceptor agonist properties of apomorphine, (+)3ppp and (-)3ppp by recording of yawning behaviour in rats
Stahle L, Ungerstedt U
Department of pharmacology, Karolinska Institute. sSockholm, Sweden


Schizophrenic morbidity has been reported to be reduced by low doses of apomorphine (APO). Such low doses of APO are considered to slectively stimulate dopamine auto receptors leading to a decrease of dopamine release. In humans it has been found thate a low, non emetic dose of APO induced yawning. APO also induced yawning in rats and the behaviour is believed tio reflect autoreceptor stimulation. Consequently it may be used to assess drugs potentially active on dopamine autoreceptors.
The presebt study was undertaken to investigate the yawning dose-ressponse to APO and the sensitivity of this yawning to sulpiride, a neuroleptic that may be a selective blocker of dopamine autorecptors at the doses tested here. The enantiomers of the recently synthetised compound 3-(3-hydroxyphenyl)-N-n-propyl piperidine (3-PPP) are believed to be active on dopamine autoreceptors and their ability to induce yawning was therefore tested. We report the inability of (-)-3-PPP to induce yawbning, while (+)-3-PPP was as efficient as APO in this respect. [...]
Discussion : The present study confirm the finding that invery low doses APO indices yawning. This has also been observed in man. Yawning in rats is believed to reflect stimulation of dopaminergic autoreceptors. Sulpiride, considered to selectively block these autoreceptors at low doses blocked this effect in a dose-dependent manner, giving evidence for the dopaminergic nature of the yawning response and its possible mediation by autoreceptors. It is not plausible that the response could be due to stimulation of peripheral dopamine receptors since domperidone does not antagonise APO induced yawning.
3-PPP has been developed as a selective autoreceptor agonist and its recent resolution into the (+)- and (-)-enantiomers revealed that (+)-3PPP may be an autoreceptor agonist at low doses while higher doses also stimulate postsynaptic receptors. Only the lower dose range was tested in the present study but our findings agree with those of Hjorth et al. (1982) concerning the autoreceptor stimulating properties of the drug. However, (-)-3-PPP did not mimic the effect of a low dose of APO in the present study. Hjorth et al. (1982) suggested that the (-)form may stimulate autoreceptors at low doses and block postsynaptic receptors at higher doses.
It was also recently reported that both enantiomers reduce exploratory locomotion when they are given intraaccumbens. The present findings give no clear evidence for autoreceptor stimulating properties of (-)-3PPP. This conclusion is also supported by the recent finding that the (+)-enantiomer, but not the (-)-enantiomer, reduced the in vivo release of dopamine and DOPAC from the striatum. Furthermore, sulpiride does not antagonize the behavioural suppression of (-)-3-PPP as is the case for other dopamine agonists). Thus, evidence from several different models used to assess stimulation of dopamine autoreceptors cast doubt upon the ability of (-)-3-PPP to stimulate dopamine autoreceptors selectively. In contrast the yawning behaviour induced by (+)-3-PPP is sensitive to sulpiride suggesting that the same mechanism is responsible for the effects of APO and (+)-3-PPP.
In summary, the present study supports the idea that yawning behaviour may be used as an index of dopamine autoreceptor stimulation. Using this model it was found that (+)-3-PP but not (-)-3-PPP may posess autoreceptor stimulating properties comparable with those of a low dose of APO.
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