Effect of 1,2,3,4,-tetrahydroisoquinoline administration under conditions of CYP2D inhibition on dopamine metabolism, level of tyrosine hydroxylase protein and the binding of [3H]GBR 12,935 to dopamine transporter in the rat nigrostriatal, dopaminergic system.
Current concepts of Parkinson's disease (PD) postulate that interaction between neurotoxins and specific genetic background may play an important role in pathogenesis of PD. Therefore, the effect of multiple administration of 1,2,3,4-tetrahydroisoquinoline (TIQ) under conditions of CYP2D blockade on the expression of key markers of PD was studied in the rat striatum (STR) and substantia nigra (SN). TIQ administered alone (50 mg/kg i.p. twice daily for 14 days) markedly decreased the level of tyrosine hydroxylase protein (TH) in the STR; however, this effect was not accompanied by reduction of dopamine (DA) concentration and [(3)H]GBR 12,935 binding to dopamine transporter (DAT). Administration of CYP2D inhibitor, quinine, jointly with TIQ lowered the levels of TH and DA in that structure, but slightly increased DAT binding. In the SN, treatment with TIQ alone did not change TH level although it enhanced DA content and decreased [(3)H]GBR 12,935 binding to DAT in the substantia nigra pars compacta (SNc). Neither the TH level nor DA concentration was affected by the combined treatment, although DAT binding was still reduced in the SN. TIQ did not change the total DA catabolism in the STR, but caused its inhibition in the SN. It strongly depressed the levels of intraneuronal DA metabolite DOPAC and enhanced that of extraneuronal 3-MT in either structure. TIQ more weakly affected the levels of both DA metabolites in the presence of quinine. Our results suggest that endogenous TIQ may act rather as neuromodulator but not as parkinsonism-inducing neurotoxin in the rat brain.
Lorenc-Koci
Elzbieta
E
Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Science, 12, Smetna St., PL 31-343 Kraków, Poland. lorenc@if-pan.krakow.pl
Antkiewicz-Michaluk
Lucyna
L
Wardas
Jadwiga
J
Zapała
Małgorzata
M
Wierońska
Joanna
J
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000429:Alcohol Oxidoreductases; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects*; D000072467:Cytochrome P450 Family 2; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D004334:Drug Administration Schedule; D004347:Drug Interactions; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010879:Piperazines / Q000493:pharmacokinetics*; D011485:Protein Binding / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D011803:Quinine / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; C493216:Slc6a3 protein, rat; D044005:Tetrahydroisoquinolines; D014316:Tritium; D015102:3,4-Dihydroxyphenylacetic Acid; C014843:1,2,3,4-tetrahydroisoquinoline; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine; D011803:Quinine; D000429:Alcohol Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; C504568:Cyp2d1 protein, rat; D000072467:Cytochrome P450 Family 2; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine