Preproenkephalin mRNA expression in the caudate-putamen of MPTP monkeys after chronic treatment with the D 2 agonist U91356A in continuous or intermittent mode of administration: comparison with l-DOPA therapy

Abstract

The effect of chronic treatment with the D 2 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 D 2 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 D 2 agonist treatments suggest that the D 1 agonist component of l-DOPA therapy opposes the D 2 agonist activity. Hence, D 1 receptor agonist activity would stimulate PPE mRNA expression whereas D 2 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.