Locomotor effects of amantadine in the mouse are not those of a typical glutamate antagonist.
Amantadine has been shown to displace [3H]MK 801 from its binding site on the NMDA receptor. We have therefore studied the motor effects of amantadine in normal and 24 h reserpine-treated mice to determine whether the behavioural profile of this drug resembles that of other NMDA receptor antagonists (e.g. MK 801). In common with the latter, amantadine (5-40 mg/kg IP) produced a modest dose-dependent sedation in dopamine-intact mice, with a reduction in locomotion and other species-typical 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 response was highly variable and not statistically significant. As with MK 801, amantadine significantly inhibited the locomotion induced by the selective D2 agonist RU 24213 (5 mg/kg SC) and the mixed D1/D2 agonist apomorphine (0.5 mg/kg SC) in monomine-depleted mice, without altering the animals' responsiveness to threshold doses of these drugs. However, amantadine did not facilitate the locomotion induced by threshold (3 mg/kg IP) or fully active doses (30 mg/kg IP) of the selective D1 agonist SKF 38393, which distinguishes amantadine from other NMDA receptor blockers. Since the potentiation of dopamine D1-dependent locomotion may be a major factor in the antiparkinson activity of MK 801 and other glutamate receptor antagonists, the inability of amantadine to potentiate SKF 38393 in this study suggests the mechanism of its anti-akinetic activity differs from that of conventional glutamate blocking drugs.
Starr
M S
MS
Department of Pharmacology, School of Pharmacy, London, United Kingdom.
Starr
B S
BS
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000547:Amantadine / Q000494:pharmacology*; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000187:drug effects; D012110:Reserpine / Q000494:pharmacology
D018491:Dopamine Agonists; D018691:Excitatory Amino Acid Antagonists; D010627:Phenethylamines; D017470:Receptors, Glutamate; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C016868:N-n-propyl-N-phenylethyl-4(3-hydroxyphenyl)ethylamine hydrochloride; D012110:Reserpine; D000547:Amantadine; D001058:Apomorphine