Effect of the NMDA receptor antagonist, MK-801, on locomotor activity and on the metabolism of dopamine in various brain areas of mice.

Various doses (0.1-0.5 mg/kg i.p.) of the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, produced a dose-dependent increase in well-coordinated locomotor activity of NMRI mice. Higher doses (greater than 0.5 mg/kg) produced a typical motor syndrome characterized by head weaving, body rolling, ataxia and salivation. MK-801, 0.2 mg/kg i.p., a dose which produced marked locomotor stimulation, increased the rate of disappearance of dopamine in the striatum and in the limbic forebrain of the animals, whereas the rate of disappearance of noradrenaline remained unchanged in the limbic forebrain and in the hippocampus. MK-801 increased the rate of tyrosine hydroxylation (measured as the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after inhibition of DOPA decarboxylase) in the striatum with no change in DOPA formation in the limbic forebrain. The levels of 3,4-dihydroxyphenylacetic acid (DOPAC) remained unchanged both in the striatum and in the limbic forebrain following the administration of MK-801. It is concluded that MK-801 may facilitate the activation of dopaminergic mechanisms through an indirect (perhaps by reducing glutamatergic activity) rather than a direct effect on dopamine neurons.