Effects of the DT-diaphorase inhibitor dicumarol on striatal monoamine levels in L-DOPA and L-deprenyl pre-treated rats.
It has been proposed that DT-diaphorase plays a strategic role as a neuroprotective enzyme for monoamine neurons, perhaps together with monoamine oxidase (MAO). Thus, we investigated the long-term effects produced by DT-diaphorase inhibition with dicumarol injected unilaterally into the medial forebrain bundle (MFB) on monoamine and metabolite levels, alone, or following dopamine loading with 3,4-dihydroxyphenyl-L-alanine (L-DOPA) or MAO inhibition with L-deprenyl. Monoamine levels were assayed in aliquots from tissue samples from right and left striatum, including both dorsal and ventral regions. Dicumarol alone produced increases in 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), but not in dopamine and metabolite levels when assayed two weeks later. However, following preloading with L-DOPA (3 x 25 mg/kg s.c. 7, 4 and 1 h before surgery), a long-lasting bilateral increase in dopamine and metabolite levels was observed after dicumarol. No effect was observed on dopamine, 5-HT and metabolite levels after L-deprenyl (3 x 10 mg/kg, s.c.) alone, but the levels were unilaterally increased when L-deprenyl was followed by dicumarol. The same result was produced when both L-deprenyl and dicumarol were injected simultaneously into the same brain region. In conclusion, the present study shows that intracerebral inhibition of DT-diaphorase produces long-term changes in 5-HT, but also in dopamine metabolism when DT-diaphorase inhibition is combined with MAO inhibition by systemic or intracerebral treatment with L-deprenyl. It is suggested that both MAO and DT-diaphorase have to be inhibited for inducing long-term changes in monoamine metabolism. Thus, DT-diaphorase is an enzyme to be taken into account when L-DOPA is used to treat Parkinson's disease, or when an MAO-inhibitor is used to treat depression.
Bustamante
Diego
D
Programme of Molecular & Clinical Pharmacology, ICBM, Medical Faculty, University of Chile, Santiago 7, Casilla 70,000, Chile.
Bustamante
L
L
Segura-Aguilar
Juan
J
Goiny
Michel
M
Herrera-Marschitz
Mario
M
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D001728:Dicumarol / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007980:Levodopa / Q000008:administration & dosage*; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000008:administration & dosage*
D015306:Biogenic Monoamines; D004791:Enzyme Inhibitors; D012642:Selegiline; D007980:Levodopa; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone)