Differential Regulation of Striatal Preproenkephalin and Preprotachykinin mRNA Levels in MPTP‐Lesioned Monkeys Chronically Treated with Dopamine D1 or D2 Receptor Agonists
Authors: Morissette Marc , Grondin Richard , Goulet Martin , Bédard Paul J. , Di Paolo Thérèse 
Published: March 2003

Abstract : Studies in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine
(MPTP)‐lesioned monkeys 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 relative contributions of the
dopamine D1 and D2 receptors for PPE mRNA regulation
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 1‐month treatment with the
D1 agonist SKF‐82958, administered subcutaneously in pulsatile or
continuous mode, compared with the long‐acting D2 agonist
cabergoline. Normal as well as untreated MPTP animals were also studied. PPE
mRNA levels were elevated in the caudate nucleus and putamen of untreated MPTP
monkeys compared 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‐putamen and more so in the medial versus the lateral parts. PPT mRNA
levels were decreased in the caudate and putamen of untreated MPTP monkeys
compared with control animals, and this was observed in the middle and
posterior parts of these brain areas. Elevated PPE and decreased PPT mRNA
levels observed after MPTP exposure were corrected after treatment with
cabergoline (0.25 mg/kg, every other day), a dose that had antiparkinsonian
effects and did not give sustained dyskinesia. In contrast, elevated PPE mRNA
levels observed in untreated MPTP monkeys were markedly increased by pulsatile
administration of SKF‐82958 (1 mg/kg, three times daily) in two monkeys in
which the parkinsonian symptoms were improved and dyskinesias developed,
whereas it remained close to control values in a third one that did not
display dyskinesias despite a sustained improvement in disability ; a shorter
duration of motor benefit (wearing off) over time was observed in these three
animals. By contrast, pulsatile administration of SKF‐82958 corrected the
decreased PPT level observed in untreated MPTP monkeys. Continuous treatment
with SKF‐82958 (equivalent daily dose) produced no clear antiparkinsonian and
dyskinetic responses and did not alter the denervation‐induced elevation of
PPE or decrease of PPT mRNA levels. The present data suggest an opposite
contribution of the dopamine D1 receptors (stimulatory) as compared
with the dopamine D2 receptors (inhibitory) on PPE mRNA, whereas a
similar stimulatory contribution of D1 or D2 receptors is observed for PPT mRNA. An increase 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 antiparkinsonian response was associated with a correction of the lesion‐induced decrease of PPT.