LOCOMOTOR EFFECTS OF AMANTADINE IN THE MOUSE ARE NOT THOSE OF A TYPICAL GLUTAMATE ANTAGONIST

Amantadine has been shown to displace [H-3]MK 801 from its binding sit e on the NMDA receptor. We have therefore studied the motor effects of amantadine in normal and 24 h reserpine-treated mice to determine whe ther the behavioural profile of this drug resembles that of other NMDA receptor antagonists (e.g. MK 801). In common with the latter, amanta dine (5-40 mg/kg IP) produced a modest dose-dependent sedation in dopa mine-intact mice, with a reduction in locomotion and other species-typ ical behaviours (e.g. rearing and grooming), but with no signs of the hyperactivity, stereotypy, ataxia or loss of muscle tone commonly seen with MK 801. Amantadine (5-80 mg/kg IP) effected a small increase in motility in akinetic reserpine-treated mice by itself, but this respon se was highly variable and not statistically significant. As with MK 8 01, amantadine significantly inhibited the locomotion induced by the s elective D-2 agonist RU 24213 (5 mg/kg SC) and the mixed D-1/D-2 agoni st apomorphine (0.5 mg/kg SC) in monomine-depleted mice, without alter ing the animals' responsiveness to threshold doses of these drugs. How ever, amantadine did not facilitate the locomotion induced by threshol d (3 mg/kg IP) or fully active doses (30 mg/kg IP) of the selective D- 1 agonist SKF 38393, which distinguishes amantadine from other NMDA re ceptor blockers. Since the potentiation of dopamine D-1-dependent loco motion may be a major factor in the antiparkinson activity of MK 801 a nd other glutamate receptor antagonists, the inability of amantadine t o potentiate SKF 38393 in this study suggests the mechanism of its ant i-akinetic activity differs from that of conventional glutamate blocki ng drugs.