RT Journal Article
SR Electronic
T1 MPP(+)-like neurotoxicity of a pyridinium metabolite derived from haloperidol: in vivo microdialysis and in vitro mitochondrial studies.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 380
OP 387
VO 268
IS 1
A1 H Rollema
A1 M Skolnik
A1 J D'Engelbronner
A1 K Igarashi
A1 E Usuki
A1 N Castagnoli, Jr
YR 1994
UL http://jpet.aspetjournals.org/content/268/1/380.abstract
AB Intracerebral (intrastriatal, intranigral and intracortical) microdialysis studies were conducted in conscious rats to investigate the comparative dopaminergic and serotonergic neurotoxic potential of the pyridinium metabolite 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium (HPP+), derived from the extensively used neuroleptic agent haloperidol and 1-methyl-4-phenylpyridinium (MPP+), the pyridinium metabolite derived from the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Although HPP+ was less potent than MPP+ on the dopaminergic system, the two compounds displayed comparable toxic effects on the serotonergic system. HPP+ also proved to be a weaker inhibitor of mitochondrial respiration than MPP+ in vivo as measured by increases in extracellular lactate levels. On the other hand, HPP+ was a more potent inhibitor of mitochondrial respiration in vitro than MPP+, with IC50 values of 12 microM (HPP+) and 160 microM (MPP+). Quantitative estimations established that the concentrations of the more hydrophobic HPP+ in the brain tissues surrounding the microdialysis probe were less than those of MPP+ after comparable perfusions. Consequently, the inherent toxicity of HPP+ relative to MPP+ may be greater than suggested by the results observed in the microdialysis experiments. These data support previous speculations that HPP+ may contribute to some of the persistent extrapyramidal side effects associated with chronic haloperidol treatment.