Differential regulation of striatal preproenkephalin and preprotachykinin mRNA levels in MPTP-lesioned monkeys chronically treated with dopamine D-1 or D-2 receptor agonists

Studies in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mon keys and In parkinsonian patients show elevated preproenkephalin (PPE) mRNA levels, unaltered by chronic L-DOPA therapy, whereas preprotachykinin (PPT ) mRNA levels are decreased by the lesion and corrected by L-DOPA. The rela tive contributions of the dopamine D-1, and D-2, receptors for PPE mRNA reg ulation were investigated in the present study and compared with those for PPT mRNA. in situ hybridization was used to measure peptide mRNA levels in the striatum of MPTP cynomolgus monkeys after chronic I-month treatment wit h the D-1, agonist SKF-82958, administered subcutaneously in pulsatile or c ontinuous mode, compared with the long-acting D-2, agonist cabergoline. Nor mal as well as untreated MPTP animals were also studied. PPE mRNA levels we re elevated in the caudate nucleus and putamen of untreated MPTP monkeys co mpared with control animals with a more pronounced increase in the lateral as compared with the medial part of both structures. PPT mRNA levels showed a rostrocaudal gradient, with higher values in the middle of the caudate-p utamen and more so in the medial versus the lateral parts. PPT mRNA levels were decreased in the caudate and putamen of untreated MPTP monkeys compare d with control animals, and this was observed in the middle and posterior p arts of these brain areas. Elevated PPE and decreased PPT mRNA levels obser ved after MPTP exposure were corrected after treatment with cabergoline (0. 25 mg/kg, every other day), a dose that had antiparkinsonian effects and di d not give sustained dyskinesia. In contrast, elevated PPE mRNA levels obse rved in untreated MPTP monkeys were markedly increased by pulsatile adminis tration of SKF-82958 (1 mg/kg, three times daily) in two monkeys in which t he parkinsonian symptoms were improved and dyskinesias developed, whereas i t remained close to control values in a third one that did not display dysk inesias despite a sustained improvement in disability; a shorter duration o f motor benefit (wearing off) over time was observed in these three animals . By contrast, pulsatile administration of SKF-82958 corrected the decrease d PPT level observed in untreated MPTP monkeys. Continuous treatment with S KF-82958 (equivalent daily dose) produced no clear antiparkinsonian and dys kinetic responses and did not alter the denervation-induced elevation of PP E or decrease of PPT mRNA levels. The present data suggest an opposite cont ribution of the dopamine D-1, receptors (stimulatory) as compared with the dopamine D-2, receptors (inhibitory) on PPE mRNA, whereas a similar stimula tory contribution of D-1, or D-2, receptors is observed for PPT mRNA. An in crease in PPE expression could be involved in the induction of dyskinesias and wearing off, whereas our data do not support this link for PPT. The ant iparkinsonian response was associated with a correction of the lesion-induc ed decrease of PPT.