Dramatic synergism between MK-801 and clonidine with respect to locomotor stimulatory effect in monoamine-depleted mice.

The present study corroborates previous findings showing that the selective, non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)-cyclohepten-5,10-imi ne] produces a dose-dependent increase in locomotion in mice pretreated with a combination of the monoamine-depleter reserpine and the catecholamine synthesis inhibitor alpha-methyl-para-tyrosine. Moreover, the present investigation demonstrates a synergistic interaction between MK-801 and the alpha-adrenergic agonist clonidine in monoamine-depleted mice: MK-801 in a dose of 1 mg/kg and clonidine in a dose of 2 mg/kg hardly affected locomotion when given separately, but when the two drugs were combined a dramatic enhancement of motor activity was observed. This effect was effectively antagonized by the alpha 2-adrenergic blockers idazoxan and yohimbine, as well as by the "atypical" neuroleptic clozapine. Likewise, a clear-cut synergism was observed when a low dose of the dopamine receptor agonist apomorphine (0.1 mg/kg), which did not per se affect motor activity, was combined with MK-801 (1.5 mg/kg); however, the synergism between apomorphine and MK-801 was less dramatic than that observed between MK-801 and clonidine. The results may have important neuropsychiatric implications related to, e.g. the treatment of Parkinson's disease and the pathogenesis of schizophrenia.