The typical
antipsychotic haloperidol is a highly effective treatment for
schizophrenia but its use is limited by a number of serious, and often irreversible, motor side effects. These
adverse drug reactions, termed extrapyramidal syndromes (EPS), result from an unknown pathophysiological mechanism. One theory relates to the observation that the
haloperidol metabolite HPP+ (4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium) is structurally similar to MPP+ (1-methyl-4-phenylpyridinium), a
neurotoxin responsible for an irreversible neurodegenerative condition similar to
Parkinson's disease. To determine whether HPP+ contributes to
haloperidol-induced EPS, we measured brain HPP+ and
haloperidol levels in strains of mice at high (C57BL/6J and NZO/HILtJ) and low (BALB/cByJ and PWK/PhJ) liability to
haloperidol-induced EPS following chronic treatment (7-10 adult male mice per strain). Brain levels of HPP+ and the ratio of HPP+ to
haloperidol were not significantly different between the
haloperidol-sensitive and
haloperidol-resistant strain groups (P=0.50). Within each group, however, strain differences were seen (P<0.01), indicating that genetic variation regulating steady-state HPP+ levels exists. Since the HPP+ levels that we observed in mouse brain overlap the range of those detected in post-mortem human brains following chronic
haloperidol treatment, the findings from this study are physiologically relevant to humans. The results suggest that strain differences in steady-state HPP+ levels do not explain sensitivity to
haloperidol-induced EPS in the mice we studied.