Effect of a pyridinium metabolite derived from haloperidol on the activities of striatal tyrosine hydroxylase in freely moving rats.
The effects of a pyridinium metabolite (HPP+) derived from haloperidol (HP) on in vivo tyrosine hydroxylation was evaluated in freely moving rats. As an index of the in vivo activity of tyrosine hydroxylase (TH), the rat striatum was perfused with NSD-1015, and extracellular 3,4-dihydroxyphenylalanine (DOPA) levels were measured. HPP+ (1 mM) gradually reduced tyrosine hydroxylation to 30% of the basal level, although the effect was less potent than 1-methyl-4-phenylpyridinium ion (MPP+). On the contrary, HPP+ at a 0.1 mM dose decreased in 5-hydroxyindoleacetic acid (5-HIAA) level, but did not affect dopamine metabolites. The present study revealed that HPP+ irreversible inhibited in vivo tyrosine hydroxylation by the same manner of MPP+. However, the neurotoxic effects of HPP+ in vivo would be selective for serotonergic over dopaminergic neurons, which distinguishes the toxic profile of this compound compared to that of MPP+.
Igarashi
K
K
Faculty of Pharmaceutical Sciences, Kobegakuin University, Kobe, Japan.
Matsubara
K
K
Kasuya
F
F
Fukui
M
M
Idzu
T
T
Castagnoli
N
N
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D006834:Hydrazines; C040692:4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-1-butanol; D006897:Hydroxyindoleacetic Acid; D004295:Dihydroxyphenylalanine; C004297:3-hydroxybenzylhydrazine; D014446:Tyrosine 3-Monooxygenase; D006220:Haloperidol; D015655:1-Methyl-4-phenylpyridinium