Since
H3 receptor (H3R) antagonists/inverse agonists can improve cognitive function in animal models, they may have the potential to be used as add-on
therapy in the treatment of
schizophrenia, a disease with significant cognitive deficits. However, a recent study showed potentiation of
haloperidol-induced
catalepsy by
ciproxifan, an
imidazole-containing H3R antagonist/inverse agonist, suggesting there is a potential risk of exacerbating extrapyramidal symptoms (EPS) if H3R antagonists were used as adjunctive treatment [Pillot, C., Ortiz, J., Heron, A., Ridray, S., Schwartz, J.C. and Arrang, J.M.,
Ciproxifan, a
histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of
haloperidol in the rat, J Neurosci, 22 (2002) 7272-80]. In order to clarify the basis of this finding, we replicated this result and extended the work with another
imidazole and two non-
imidazole H3R antagonists. The results indicate that
ciproxifan significantly augmented the effects of
haloperidol and
risperidone on
catalepsy. Another
imidazole H3R antagonist,
thioperamide, also potentiated the effect of
risperidone on
catalepsy. In contrast, no
catalepsy-enhancing effects were observed when selective non-
imidazole H3R antagonists,
ABT-239 and A-431404, were coadministered with
haloperidol and/or
risperidone. As
ciproxifan and
thioperamide are inhibitors of
cytochrome P450 enzymes, responsible for metabolizing
risperidone and
haloperidol, the possibility that the augmentation of
antipsychotics by
imidazoles resulted from
drug-drug interactions was tested. A
drug metabolism study revealed that an
imidazole, but not a non-
imidazole, potently inhibited the metabolism of
haloperidol and
risperidone. Furthermore,
ketoconazole, an
imidazole-based CYP 3A4 inhibitor, significantly augmented
risperidone-induced
catalepsy. Together, these data suggest the potentiation of
antipsychotic-induced
catalepsy may result from pharmacokinetic
drug-drug interactions and support the potential utility of non-
imidazole H3R antagonists in treatment of
cognitive impairment in
schizophrenia without increased risk of increased EPS in patients.