MK-801 potentiates antidystonic effects of clozapine but not of haloperidol in mutant dystonic hamsters.
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.
Richter
A
A
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Löscher
W
W
D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000494:pharmacology*; D002375:Catalepsy / Q000139:chemically induced; D003024:Clozapine / Q000494:pharmacology*; D006224:Cricetinae / Q000235:genetics; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004357:Drug Synergism; D004421:Dystonia / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D009154:Mutation; D018696:Neuroprotective Agents / Q000494:pharmacology*
D018726:Anti-Dyskinesia Agents; D018696:Neuroprotective Agents; D016291:Dizocilpine Maleate; D003024:Clozapine; D006220:Haloperidol