INCREASED PROENKEPHALIN MESSENGER-RNA LEVELS IN THE RAT NEOSTRIATUM FOLLOWING LESION OF THE IPSILATERAL NIGROSTRIATAL DOPAMINE PATHWAY WITH 1-METHYL-4-PHENYLPYRIDINIUM ION (MPP+) - REVERSAL BY EMBRYONIC NIGRAL DOPAMINE GRAFTS

In situ hybridization studies were performed to study the changes in proenkephalin mRNA levels in the neostriatum of rats with long-term (18 months) unilateral lesions of the nigrostriatal dopamine (DA) pathway induced by 1-methyl-4-phenylpyridinium ion (MPP+) and in animals bearing embryonic DA grafts implanted into the DA depleted striatum. In the ipsilateral striatum of MPP+ -lesioned animals, there was a 2-fold increase in the levels of proenkephalin mRNA compared with those in the contralateral striatum of the same animals or the ipsilateral striatum of control animals. High resolution analysis using emulsion autoradiography showed that increase in proenkephalin gene expression in response to DA-denervation by MPP+ was due to an increase in the hybridization signal over individual expressing cells as well as to an increase in the number of labelled cells. In the DA-grafted striatum the levels of proenkephalin mRNA were significantly (P < 0.01) reduced when compared with those in the MPP+ -lesioned striatum due to both a decrease in the number of labelled cells as well as the hybridization density per individual cell. Moreover, when compared with the ipsilateral striatum of control animals, the levels of proenkephalin mRNA in the DA-grafted striatum was slightly lower due to a 20% decrease in the number of labelled cells rather than a decrease in the hybridization signal per individual cell. The results of this study are important in two respects. Firstly, they clearly show that the increase in proenkephalin gene expression in the striatum of rats with complete nigrostriatal DA lesions, can be maintained for many months after the lesion. Secondly, this increase in proenkephalin gene expression can be completely reversed by embryonic DA grafts which extensively reinnervate the DA-depleted striatum and make synaptic connections with the intrinsic striatal enkephalinergic neurons. The results indicate that the nigral DA neurons exert a tonic inhibitory influence on the activity of proenkephalin mRNA-containing neurons in the straitum.