Influence of monoamine oxidase inhibitors on striatonigral dynorphin system: a study with deprenyl and clorgyline.
This study examined the influence of selected monoamine oxidase (MAO) inhibitors on basal ganglia neurotransmitters (dopamine and 5-hydroxytryptamine) and neuropeptide (dynorphin) systems of Sprague-Dawley rats. The striatum or substantia nigra or both were used for biochemical determinations. The striatal concentrations of DA, 5-hydroxytryptamine (5-HT) and their metabolites were determined by HPLC. The levels of striatal and nigral dynorphin A (1-8) (DYN) were determined by radioimmunoassay. The abundance of striatal prodynorphin (PD) mRNA was determined by Northern blot analysis using a cRNA probe. Deprenyl, a MAO-B selective inhibitor (0.25, 0.5, 5, 10 or 20 mg/kg/day, subcutaneously (s.c.) for 4 d) and clorgyline, a MAO-A inhibitor (0.5, 5, 10 or 20 mg/kg/day, s.c. for 4 d) produced a dose-related increase in DA and 5-HT and a decrease in their metabolites in the striatum. Only high doses (20 mg/kg) of deprenyl or clorgyline induced an increase in DYN levels in the striatum and substantia nigra (DYN terminal region); the increased level of DYN was accompanied by an increase in PD-mRNA levels in striatum (DYN cell-body region). Co-administration of low doses (2.5 mg/kg/day, s.c. for 4 d) of deprenyl and clorgyline, that would selectively inhibit MAO-B and MAO-A respectively, produced a marked increase in DA and 5-HT, a decrease in DOPAC and 5-HIAA, an increase in DYN levels in the striatum and substantia nigra and an increase in PD-mRNA levels in the striatum. The results indicate that concurrent inhibition of MAO-B and MAO-A, that results in markedly elevated levels of DA and 5-HT in the striatum, is associated with an increase in dynorphin biosynthesis in the striatonigral neurons.
Sivam
S P
SP
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Gary 46408.
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D003010:Clorgyline / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004399:Dynorphins / Q000378:metabolism*; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism
D008996:Monoamine Oxidase Inhibitors; D012333:RNA, Messenger; D015102:3,4-Dihydroxyphenylacetic Acid; D012642:Selegiline; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D004399:Dynorphins; D003010:Clorgyline; D004298:Dopamine