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.
Carlsson
M
M
Department of Pharmacology, University of Göteborg, Sweden.
Carlsson
A
A
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism / Q000502:physiology*; D003000:Clonidine / Q000494:pharmacology*; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D016291:Dizocilpine Maleate; D004347:Drug Interactions; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D011954:Receptors, Dopamine / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D012110:Reserpine / Q000494:pharmacology
D000927:Anticonvulsants; D015306:Biogenic Monoamines; D003986:Dibenzocycloheptenes; D011954:Receptors, Dopamine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D016291:Dizocilpine Maleate; D012110:Reserpine; D003000:Clonidine