Postsynaptic dopamine agonistic effects of 3-PPP enantiomers revealed by bilateral 6-hydroxy-dopamine lesions and by chronic reserpine treatment in rats

Abstract

The motor effects of some DA autoreceptor agonists and apomorphine in rats with bilateral 6-hydroxydopamine lesions of the median forebrain bundle were studied. Whereas (-)-3-PPP, (+)-3-phenethyl-PP and EMD 23448 decreased motility in sham-operated controls, a pronounced hypermotility was induced in 6-OHDA-lesioned rats. 3-PPP enantiomers and apomorphine had similar potency as that found in test models for DA autoreceptor activity in normal rats, e.g. motility inhibition. The DA receptor involvement in the effect of (-)-3-PPP was confirmed by neuroleptic antagonism. (-)-3-PPP and EMD 23448 had similar intrinsic activity as apomorphine, whereas (+)-3-phenethyl-PP and (+)-3-PPP had lower maximal effect. However, the DA autoreceptor agonists differed from apomorphine: The development of postsynaptic supersensitivity to these drugs appeared 4-7 days after the lesion compared to 1-2 days for apomorphine and (+)-3-PPP. Furthermore, no active oral stereotypy was induced by the autoreceptor selective compounds in contrast to the effect observed after apomorphine and (+)-3-PPP. In a separate experiment using circling behaviour in unilaterally 6-OHDA-lesioned rats the different time-course of appearance of supersensitivity to (-)-3-PPP, (+)-3-PPP and apomorphine was confirmed. After chronic reserpine treatment a similar postsynaptic supersensitivity to (-)-3-PPP was observed with a development time between 4 and 7 days and with a similar intensity as that observed in 6-OHDA-lesioned rats. In contrast, after chronic neuroleptic treatment for 12 days, (-)-3-PPP was unable to induce hyperactivity 3-7 days after withdrawal. The results indicate that DA autoreceptor agonists are able to stimulate postsynaptic DA receptors in conditions without endogenous transmitter supply for at least 4-7 days, but not after chronic receptor blockade in a similar period. This should lead to consideration of DA autoreceptor agonists as potential antiparkinsonian drugs without stimulant effects on normosensitive postsynaptic DA receptors.