Muscarinic antagonists in substantia nigra influence the decarboxylation of L-dopa in striatum.
This study was designed to investigate whether anticholinergic drugs acting at the level of the substantia nigra can affect basal extracellular dopamine concentrations and the levodopa (L-dopa)-induced increases in dopamine levels in the striatum. Dual probe in vivo microdialysis in freely moving rats was used. One microdialysis probe was implanted in the substantia nigra and the other in the ipsilateral striatum. Muscarinic receptor antagonists were perfused into the substantia nigra and changes in neurotransmitter levels in the substantia nigra and at the axon terminals in the striatum were monitored simultaneously. Nigral perfusion of the non-selective muscarinic receptor antagonist trihexyphenidyl (1 mM) produced an increase in extracellular dopamine and gamma-aminobutyric acid (GABA) levels in the substantia nigra. Perfusion with the muscarinic M(1) receptor antagonist telenzepine (0.1 microM) produced a significant decrease in nigral dopamine and GABA levels in the substantia nigra. The muscarinic M(2) receptor antagonist methoctramine (75 microM) produced an increase in dopamine levels in the substantia nigra. No significant changes in nigral extracellular GABA levels were observed. The L-dopa-induced increases in extracellular dopamine levels in the striatum were clearly attenuated under nigral perfusion of these drugs. This in vivo study demonstrates that anticholinergic drugs perfused at the level of the substantia nigra can modulate dopamine and GABA levels and attenuate the L-dopa decarboxylation in the striatum, possibly via modulation of the nigrostriatal dopaminergic system. We add further evidence that the substantia nigra is an important site of action of antimuscarinic drugs. The attenuation of L-dopa-induced dopamine release in the striatum exerted by nigral perfusion of these antimuscarinic drugs is probably mediated via different mechanisms. This attenuation is regarded as a beneficial effect of the muscarinic antagonists as adjuncts to L-dopa in Parkinson's disease treatment. We postulate that drugs that enhance dopamine release, after L-dopa administration, in a less extreme way than L-dopa administered on its own could prevent further neurodegeneration and dyskinesias thought to result from extremely high extracellular dopamine levels following L-dopa treatment.
Izurieta-Sánchez
P
P
Department of Pharmaceutical Chemistry and Drug Analysis, Pharmaceutical Institute, Vrije Universiteit Brussel, Laarbeeklaan, 103, B-1090, Brussels, Belgium.
Sarre
S
S
Ebinger
G
G
Michotte
Y
Y
D000704:Analysis of Variance; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003653:Decarboxylation; D003959:Diamines / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D005110:Extracellular Space; D007980:Levodopa / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010276:Parasympatholytics / Q000494:pharmacology; D010477:Perfusion; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014282:Trihexyphenidyl / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D003959:Diamines; D018727:Muscarinic Antagonists; D018377:Neurotransmitter Agents; D010276:Parasympatholytics; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C046338:telenzepine; D010890:Pirenzepine; D007980:Levodopa; D005680:gamma-Aminobutyric Acid; D014282:Trihexyphenidyl; C054938:methoctramine; D004298:Dopamine