Reduced striatal tyrosine hydroxylase activity is not accompanied by change in responsiveness of dopaminergic receptors following chronic treatment with deprenyl.
Deprenyl is the only selective monoamine oxidase B (MAO-B) inhibitor that is in clinical use for the treatment of Parkinson's disease. Our previous studies showed that chronic treatment of rats with low (MAO-B selective) doses of deprenyl inhibited dopamine (DA) re-uptake and enhanced DA release in the striatum. These changes could affect DA synthesis rate by activation of negative feedback loops. Chronic deprenyl treatment has also been suggested to cause down-regulation of release-modulating DA receptors. The effects of chronic and acute treatment with deprenyl on ex vivo striatal tyrosine hydroxylase activity were therefore studied, by determination of steady-state tissue level of DOPA following administration of NSD-1015 (100 mg/kg i.p.). In addition, we assessed changes in the in vivo sensitivity of dopaminergic receptors from the reduction in DOPA extracellular level after systemic apomorphine administration (2.5 mg/kg s.c.), following elevation of microdialysate DOPA by systemic or local aromatic amino acid decarboxylase inhibition with NSD-1015. Chronic treatment with deprenyl (0.25 mg/kg s.c. daily for 21 days) caused a significant reduction in tyrosine hydroxylase activity to 60% of control, with no change in the apomorphine-induced reduction of microdialysate DOPA and DOPAC. The reduction in tyrosine hydroxylase activity is compatible with our previous results showing an increase in striatal DA extracellular level following chronic treatment with deprenyl. The increased extracellular striatal DA level could reduce tyrosine hydroxylase activity through activation of a negative feedback loop, by activation of either presynaptic or postsynaptic DA receptors.
Lamensdorf
I
I
Pharmacology Unit, Rappaport Family Faculty of Medicine, Technion, Haifa, Israel.
Finberg
J P
JP
D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects*; D012642:Selegiline / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D014793:Visual Cortex / Q000187:drug effects* / Q000201:enzymology
D004791:Enzyme Inhibitors; D006834:Hydrazines; D008996:Monoamine Oxidase Inhibitors; D011954:Receptors, Dopamine; D012642:Selegiline; C004297:3-hydroxybenzylhydrazine; D014446:Tyrosine 3-Monooxygenase