MK-801 potentiates antidystonic effects of clozapine but not of haloperidol in mutant dystonic hamsters

Abstract

The interaction of nigrostriatal dopamine and corticostriatal glutamate plays a critical role in motor output. Recent studies in mutant dystonic hamsters ( dt sz ), an animal model of idiopathic generalized dystonia, revealed antidystonic effects of both N-methyl- d-aspartate (NMDA) receptor antagonists, such as dizocilpine (MK-801), and of neuroleptics, such as haloperidol and clozapine. Whereas the neuroleptics reduced spontaneous locomotion at antidystonic effective doses, MK-801 caused hyperactivity in mutant hamsters. Therefore, the combination of neuroleptics and MK-801 may exhibit synergistic antidystonic effects, while the side effects may be counteracted. In order to prove this assumption, the neuroleptics haloperidol and clozapine were coadministered with MK-801 in dt sz hamsters in the present study. The antidystonic effects were potentiated by coadministration of MK-801 and clozapine, but not by the combination of MK-801 and haloperidol. The coadministration of MK-801 and clozapine did not cause severe side effects, such as catalepsy in dystonic hamsters. In contrast to the well-documented reverse of haloperidol-induced catalepsy by MK-801 in rats, in mutant hamsters, catalepsy was increased by coadministration of haloperidol and MK-801. This unexpected finding could be due to pathophysiological brain alterations in dt sz hamsters, because in non-dystonic control hamsters, combined treatment with MK-801 and haloperidol did not cause cataleptogenic effects.