PREPROENKEPHALIN MESSENGER-RNA 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

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 cynomolg us monkeys Macaca fascicularis rendered parkinsonian by 1-methyl-4-phe nyl-1,2,3,6-tetrahydropyridine (MPTP). In MPTP monkeys, pulsatile trea tment with either L-DOPA or U91356A relieved parkinsonian symptoms but caused progressive sensitization to treatment and, as expected, induc ed choreic dyskinesias. Tn contrast, U91356A given in a continuous mod e led to partial behavioral tolerance without appearance of dyskinesia s. Using in situ hybridization histochemistry, lesioning was shown to produce elevation of PPE mRNA levels in the lateral and medial parts o f the putamen and in the lateral part of the caudate nucleus compared to control animals at the three rostrocaudal regions analyzed. In gene ral, no change of PPE mRNA levels were observed in the medial caudate after MPTP lesioning with or without L-DOPA or U91356A treatments in t he three rostrocaudal regions measured except for an increase in the c audal part of L-DOPA-treated MPTP monkeys. Tn the putamen and lateral caudate nucleus, elevated PPE mRNA expression by MPTP generally was no t corrected (or only partially corrected) by chronic L-DOPA treatment except for the rostral medial putamen where correction to control valu es was observed. In general, pulsatile administration of U91356A parti ally corrected the lesion-induced elevation of PPE mRNA levels in the putamen and lateral caudate nucleus whereas the correction was more pr onounced and widespread when MPTP monkeys received the continuous admi nistration of this drug. These results indicate that the mode of admin istration of a D-2 dopamine receptor agonist, such as U91356A, althoug h at a roughly equivalent dosage influences the extent of inhibition o f the expression of PPE in the denervated striatum of monkeys. In addi tion, the general lack of correction of the MPTP-induced increase of P PE mRNA in the striatum of L-DOPA-treated monkeys compared to the decr eases observed with the D-2 agonist treatments suggest that the D-1 ag onist component of L-DOPA therapy opposes the D-2 agonist activity. He nce, 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 dis playing dyskinesias had elevated striatal PPE mRNA levels whereas the MPTP monkeys with the lowest striatal PPE mRNA levels developed tolera nce without dyskinesias. (C) 1997 Elsevier Science B.V.