The effect of chronic treatment with the D2
dopamine agonist U91356A or
L-DOPA therapy on the regulation of
preproenkephalin (PPE)
mRNA was investigated in the caudate-putamen of previously
drug-naive cynomolgus monkeys Macaca fascicularis rendered parkinsonian by
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP). In
MPTP monkeys, pulsatile treatment with either
L-DOPA or
U91356A relieved parkinsonian symptoms but caused progressive sensitization to treatment and, as expected, induced choreic
dyskinesias. In contrast,
U91356A given in a continuous mode led to partial behavioral tolerance without appearance of
dyskinesias. Using in situ hybridization histochemistry, lesioning was shown to produce elevation of PPE
mRNA levels in the lateral and medial parts of the putamen and in the lateral part of the caudate nucleus compared to control animals at the three rostrocaudal regions analyzed. In general, no change of PPE
mRNA levels were observed in the medial caudate after
MPTP lesioning with or without
L-DOPA or
U91356A treatments in the three rostrocaudal regions measured except for an increase in the caudal part of
L-DOPA-treated
MPTP monkeys. In the putamen and lateral caudate nucleus, elevated PPE
mRNA expression by
MPTP generally was not corrected (or only partially corrected) by chronic
L-DOPA treatment except for the rostral medial putamen where correction to control values was observed. In general, pulsatile administration of
U91356A partially corrected the lesion-induced elevation of PPE
mRNA levels in the putamen and lateral caudate nucleus whereas the correction was more pronounced and widespread when
MPTP monkeys received the continuous administration of this
drug. These results indicate that the mode of administration of a D2
dopamine receptor agonist, such as
U91356A, although at a roughly equivalent dosage influences the extent of inhibition of the expression of PPE in the denervated striatum of monkeys. In addition, the general lack of correction of the
MPTP-induced increase of PPE
mRNA in the striatum of
L-DOPA-treated monkeys compared to the decreases observed with the D2 agonist treatments suggest that the D1 agonist component of
L-DOPA therapy opposes the D2 agonist activity. Hence, D1 receptor agonist activity would stimulate PPE
mRNA expression whereas D2 receptor agonists inhibit the expression of this
peptide. Increases in PPE expression in the striatum may be implicated in the induction of
dyskinesias since both groups of treated
MPTP monkeys displaying
dyskinesias had elevated striatal PPE
mRNA levels whereas the
MPTP monkeys with the lowest striatal PPE
mRNA levels developed tolerance without
dyskinesias.