CHRONIC BLOCKADE OF MUSCARINIC CHOLINERGIC RECEPTORS BY SYSTEMIC TRIHEXYPHENIDYL (ARTANE(R)) ADMINISTRATION MODULATES BUT DOES NOT MEDIATE THE DOPAMINERGIC REGULATION OF STRIATAL PREPROPEPTIDE MESSENGER-RNA EXPRESSION

A striatal dopaminergic denervation leads to changes in the expression of messenger RNA encoding prepropeptides contained in striatal effere nt neurons. Such a dopaminergic lesion also abolishes a functional equ ilibrium between dopaminergic and cholinergic transmissions, generally believed to operate within the neostriatum, which constitutes the the oretical basis for the clinical use of antimuscarinic drugs in extrapy ramidal diseases. It is possible, therefore, that changes in prepropep tide messenger RNA expression are mediated by an alteration in choline rgic transmission. To test this hypothesis, we have examined in rats w hether trihexyphenidyl, an antimuscarinic drug of wide clinical use, c an counteract the changes in preproenkephalin, preprotachykinin and pr eprodynorphin messenger RNA expression produced by a unilateral 6-hydr oxydopamine lesion of substantia nigra dopaminergic neurons. Two weeks after the lesion, trihexyphenidyl was continuously administered throu gh an osmotic minipump (5 mg/day for 15 days) to half of the lesioned and sham-operated rats, the other half receiving the vehicle. Using qu antitative in situ hybridization histochemistry, messenger RNAs were a nalysed at two rostrocaudal levels (anterior and central) of the neost riatum. In parallel, M(1) muscarinic receptors were measured by autora diography of [H-3]pirenzepine binding sites. In sham-operated rats, tr ihexyphenidyl administration produced a significant increase (17-27%) in M(1) binding sites. In addition, preproenkephalin messenger RNA lev els were decreased (-38%) in the central part, while preprodynorphin m essenger RNA levels were significantly increased (+22%) at both striat al levels. In 6-hydroxydopamine-lesioned rats, the expected changes in messenger RNAs were observed when ipsi- versus contralateral side val ues were compared, but changes were not always detected when compariso n was established between values from the dopamine-denervated neostria tum and those from sham-operated rats. The trihexyphenidyl administrat ion in 6-hydroxydopamine-lesioned animals was unable to reproduce the up-regulation of M(1) receptors, even in the intact neostriatum. This antimuscarinic treatment further increased preproenkephalin messenger RNA levels in the denervated anterior neostriatum, amplifying the ipsi - versus contralateral difference. It also potentiated the imbalance i n preprotachykinin messenger RNA expression, mainly as a result of an increase of preprotachykinin messenger RNA levels in the intact neostr iatum. In contrast, trihexyphenidyl treatment by increasing preprodyno rphin messenger RNA in both neostriata abolished the ipsi- versus cont ralateral difference observed in lesioned rats. In conclusion, with th e exception of preprodynorphin messenger RNA, trihexyphenidyl treatmen t was unable to counteract the imbalance in prepropeptide messenger RN A expression produced by a unilateral striatal dopaminergic denervatio n and even amplified this effect. These results question the neostriat um as the site of action of antimuscarinic drugs in producing their th erapeutic effect in extrapyramidal syndromes.