Locomotor effects of amantadine in the mouse are not those of a typical glutamate antagonist

Abstract

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.

DNA damage in brain cells and behavioral deficits in mice after treatment with high doses of amantadine

“…The behavior of the mice observed here is consistent with previous studies, which have reported cognitive deficits after administration of high doses of AMA (Fujiwara et al, 1985;Starr and Starr, 1995). In the animals it was demonstrated that AMA 50 mg kg -1 i.p., tended to exhibit decreased ambulation and rearings.…”

“…In a similar evaluation using open field, AMA (5-40 mg kg -1 ) reduced locomotion and other species-typical behaviors (e.g. rearing and grooming) in mice (Starr and Starr, 1995). Here, AMA (as a 60 mg kg -1 dose) decreased rearings and crossings in an open field, suggesting an impairing effect in exploration and locomotion in mice (Fig.…”

“…injection of saline solution or AMA (15, 30 or 60 mg kg -1 ) in a volume of 10 ml kg -1 body weight. Amantadine was administered 20 min before the session training for these behavioral procedures, based on previous studies (Fujiwara et al, 1985;Starr and Starr, 1995;Fredriksson et al, 2001).…”

6-Hydroxydopamine lesion of locus coeruleus and the antiparkinsonian potential of NMDA-receptor antagonists in rats

“…This may be quite unexpected because non-competitive NMDAreceptor antagonists are known to stimulate motor activity in intact animals and in animal models of PD. On the other hand, several studies have recently demonstrate inhibitory effects of amantadine on spontaneous locomotion in navie-but not in monoamine depleted mice and rats (Moryl et al, 1993;Starr and Starr, 1995). For that reason it has been suggested that enhanced locomotion (over a corresponding control level) after amantadine treatment does only occur, if additionally a dopaminergic hypofunction is given (Danysz et al, 1994a).…”

Antiparkinsonian actions of glutamate antagonists — alone and with L-DOPA: A review of evidence and suggestions for possible mechanisms

“…In the latter experiments the response to LY 171555 was also antagonised by raclopride and haloperidol, but not by idazoxan or ritanserin, confirming that LY 171555's action was indeed mediated by dopamine D 2 receptors, and not by %-adrenoceptors or 5HT2 receptors. Amantadine (10-20mg/kg) failed to interact with bromocriptine (2.5-5mg/kg; Skuza et al, 1994), but a higher dose of amantadine (40mg/kg) was just sufficient to inhibit RU 24213-induced movements (Start and Start, 1995). In other experiments, the systemic administration of PCP (8-32mg/kg), CGP 40116 (4-10mg/kg) and HA 966 (2-10mg/kg), also abolished RU 24213-induced motility, whilst memantine (5-40mg/kg), dextromethorphan (10-40mg/kg), CPP (l-5mg/ kg) and NBQX (0.2-25mg/kg) were without effect (Kaur and Starr, 1995a,b;Starr and Start, 1993a).…”