Effect of trihexyphenidyl, a non-selective antimuscarinic drug, on decarboxylation of L-dopa in hemi-Parkinson rats.
In vivo microdialysis was used to study the effect of the non-selective muscarinic antagonist, trihexyphenidyl, on the decarboxylation of levodopa (L-dopa) in the striatum of hemi-Parkinson rats. In normal rats, continuous perfusion of trihexyphenidyl (1 mM) via the microdialysis probe induced a significant increase in striatal dopamine release, followed by a decrease to below baseline values. A similar effect was observed, though less pronounced, in denervated striatum of rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. In these hemi-Parkinson rats, continuous striatal perfusion of trihexyphenidyl had no effect on the biotransformation of locally applied L-dopa (2 microM for 20 min) to dopamine in either intact or denervated striatum. However, systemic administration of trihexyphenidyl (1.5 mg/kg i.p.) produced an attenuation of the L- dopa-induced dopamine release in the intact striatum (contralateral to the lesion) of hemi-Parkinson rats. This effect was absent in the denervated striatum of these animals. We confirmed that L-dopa induces an increase in striatal dopamine output which is influenced by the severity of the dopaminergic denervation. The absence of an effect of trihexyphenidyl locally applied in the striatum, on biotransformation of L-dopa suggests that the site of action of antimuscarinic drugs may not be in the striatum and, therefore, remains unclear. The mechanism of action of these drugs is not well understood but appears more complicated than previously thought.
Department of Pharmaceutical Chemistry and Drug Analysis, Pharmaceutical Institute, Vrije Universiteit Brussel, Brussels, Belgium.
P
P
Izurieta-Sánchez
S
S
Sarre
G
G
Ebinger
Y
Y
Michotte
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003653:Decarboxylation; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D017551:Microdialysis; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects; D014282:Trihexyphenidyl / Q000494:pharmacology*
D000978:Antiparkinson Agents; D018727:Muscarinic Antagonists; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D014282:Trihexyphenidyl; D016627:Oxidopamine; D004298:Dopamine; D006719:Homovanillic Acid