NEUROPEPTIDE MESSENGER-RNA EXPRESSION IN THE 6-HYDROXYDOPAMINE-LESIONED RAT STRIATUM REINNERVATED BY FETAL DOPAMINERGIC TRANSPLANTS - DIFFERENTIAL-EFFECTS OF THE GRAFTS ON PREPROENKEPHALIN, PREPROTACHYKININ AND PRODYNORPHIN MESSENGER-RNA LEVELS

In situ hybridization histochemistry was used to analyse the expressio n of the messenger RNAs encoding for enkephalin, substance P and dynor phin in the striatum of normal rats, rats subjected to a unilateral 6- hydroxydopamine lesion of the mesostriatal dopamine pathway and lesion ed rats bearing intrastriatal transplants of fetal nigral neurons. Abo ut half of the rats in each group received twice-daily subcutaneous in jections of 5 mg/kg apomorphine and the other half received control in jections of saline, for nine days. Three hours after the last injectio n, the rats were killed by decapitation. Cryostat sections through the striatum were incubated with, S-35-labeled oligodeoxyribonucleotide p robes hybridizing with preproenkephalin, preprotachykinin or prodynorp hin messenger RNA. One additional series of sections was incubated wit h [H-3]GBR 12935 in order to label dopamine uptake sites. Quantitative evaluation of the hybridization signal was performed both at the macr oscopic level (autoradiographic film analysis) and at the cellular lev el (optical density of silver grains over identified cells). The graft ed nigral neurons reversed the lesion-induced up-regulation of preproe nkephalin messenger RNA in the whole striatal complex. By contrast, th e graft-induced effect on the lesion-induced down-regulation of prepro tachykinin messenger RNA was restricted to the region of the host stri atum where the graft-derived dopamine fibers exhibited their densest d istribution (up to 0.5 mm from the border of the grafts). However, fol lowing chronic treatment with apomorphine, preprotachykinin messenger RNA expression approached control levels in a wider portion of the gra fted striata (up to 1 mm from the border of the grafts). Basal prodyno rphin messenger RNA expression, which was also down-regulated in the l esioned striata, was only partially restored by the transplants. Repea ted injections of apomorphine enhanced prodynorphin messenger RNA in t he lesioned striata to levels several fold higher than normal. This ma ssive increase in prodynorphin messenger RNA expression was completely prevented by the transplants over a large volume of the host striatum (> 1 mm from the graft-host border), but a trend towards an abnormall y high prodynorphin messenger RNA expression was still present in peri pheral striatal areas that were not reached by graft-derived dopamine fibers. The present results indicate that fetal nigral neurons transpl anted to the 6-hydroxydopamine-lesioned striatum have differential eff ects on the activity of enkephalin-containing (i.e. mainly striatopall idal) and substance P- or dynorphin-containing (i.e. mainly striatonig ral) neurons. An inhibitory control over the activity of striatopallid al neurons is completely restored by the grafts, even in non-reinnerva ted striatal regions, suggesting that neurohumoral mechanisms underlie this effect. A facilitatory control over the activity of striatonigra l neurons is restored by the grafts only in the densely reinnervated p ortion of the host striatum, which indicates that synaptic transmissio n is likely to mediate this effect, The ability of the grafts to preve nt an abnormal up-regulation of prodynorphin messenger RNA expression by apomorphine indicates, however, that graft-derived dopamine release is also sufficient to induce a complete and widespread normalization of dopamine receptor sensitivity on striatonigral neurons.