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 t hat is in clinical use for the treatment of Parkinson's disease. Our p revious studies showed that chronic treatment of rats with low (MAO-B selective) doses of deprenyl inhibited dopamine (DA) re-uptake and enh anced DA release in the striatum. These changes could affect DA synthe sis rate by activation of negative feedback loops. Chronic deprenyl tr eatment has also been suggested to cause down-regulation of release-mo dulating DA receptors. The effects of chronic and acute treatment with deprenyl on ex vivo striatal tyrosine hydroxylase activity were there fore studied, by determination of steady-state tissue level of DOPA fo llowing administration of NSD-1015 (100 mg/kg i.p.). In addition, we a ssessed changes in the in vivo sensitivity of dopaminergic receptors f rom the reduction in DOPA extracellular level after systemic apomorphi ne administration (2.5 mg/kg s.c.), following elevation of microdialys ate DOPA by systemic or local aromatic amino acid decarboxylase inhibi tion with NSD-1015. Chronic treatment with deprenyl(0.25 mg/kg s.c. da ily for 21 days) caused a significant reduction in tyrosine hydroxylas e activity to 60% of control, with no change in the apomorphine-induce d reduction of microdialysate DOPA and DOPAC. The reduction in tyrosin e hydroxylase activity is compatible with our previous results showing an increase in striatal DA extracellular level following chronic trea tment with deprenyl. The increased extracellular striatal DA level cou ld reduce tyrosine hydroxylase activity through activation of a negati ve feedback loop, by activation of either presynaptic or postsynaptic DA receptors. (C) 1997 Published by Elsevier Science Ltd.