Are NMDA antagonistic properties relevant for antiparkinsonianlike activity in rats?—Case of amantadine and memantine

Abstract

Amantadine (25, 50, 100 mg/kg), memantine (5, 10, 20 mg/kg) and MK-801 (0.05, 0.1, 0.2 mg/kg), all having NMDA channel blocking properties, were compared in three tests used for screening of antiparkinsonian agents in rats, namely: haloperidol-induced catalepsy, locomotor activity in monoamine depleted rats and rotation in rats with a unilateral substantia nigra lesion. Additionally, plasma levels of amantadine and memantine were assessed to gain an insight into the concentration ranges achieved at behaviorally active doses. Amantadine and (+)-MK-801 produced dose-dependent inhibition of haloperidol-induced catalepsy while memantine was less efficacious producing clear-cut anticataleptic action at a dose of 10 mg/kg only but failing at 20 mg/kg due to myorelaxant activity. All agents attenuated sedation in monoamine depleted rats with amantadine being the least and MK-801 being the most effective. The same rank order of efficacy was seen in inducing ipsilateral rotations in rats after a substantia nigra lesion. On the basis of the present study and published data, it can be assumed that the doses of amantadine, memantine and MK-801 showing antiparkinsonian-like activity in animals result in plasma levels leading to NMDA antagonism. However, in the haloperidol-induced catalepsy test the efficacy of amantadine was higher than memantine, while the opposite was true for rotation and reserpine-induced sedation indicating pharmacodynamic differences between both agents.

Effects of memantine and MK‐801 on NMDA‐induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices

“…Memantine (1-amino-3,5-dimethyladmantane) is an uncompetitive NMDA (N-methyl-D-aspartate) receptor antagonist (Kornhuber et al, 1989;1991;Bormann, 1989;Chen et al, 1992;Parsons et al, 1993;1995a, b) that has been used clinically for many years in the treatment of spasticity and to a lesser exent Parkinson's disease (Grossmann & Schutz, 1982;Wesemann et al, 1983;Schneider et al, 1984;Kornhuber et al, 1994;Danysz et al, 1994a;. More recently, doses of this compound predicted to act selectively at NMDA receptors in vivo have been found to produce symptomatological improvements in the therapy of dementia (Ditzler, 1991;G6rtelmeyer & Erbler, 1992;Pantev et al, 1993).…”

Establishment of a novel experimental protocol for drug-induced seizure liability screening based on a locomotor activity assay in zebrafish

“…The psychotropic mechanism of action induced by amantadine treatment has been thought to be due to N-methyl-D-aspartic acid (NMDA)-receptor antagonism, and other potent NMDA antagonist, MK-801, also induced hyperlocomotion in rodents (Löscher and Hönack, 1992) and hyperactivity in zebrafish (Chen et al, 2010). Although memantine, another NMDA antagonist, failed to induce hyperactivity in zebrafish (Chen et al, 2010), the false negative results in the present study for amantadine may be related to its potency for NMDA-antagonism (Wenk et al, 1995) or due to pharmacodynamic differences (Danysz et al, 1994). Cisplatin, an anti-cancer agent, occasionally induced seizures in patients (Steeghs et al, 2003), and there have also been reports indicating its potential to induce seizures at hyponatremic conditions (Cheng et al, 2011).…”

Amantadine increases aromatic 1L-amino acid decarboxylase mRNA in PC12 cells

“…More recently, it has been shown that amantadine increases DA turnover in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice (Rojas et al, 1993) and that it increases rat striatal AADC activity (Fisher et al, 1998). In addition, amantadine produces a uncompetitive blockade of the NMDA receptor (Danysz et al, 1994(Danysz et al, , 1997) that correlated well with the increases in striatal AADC activity (Hadjiconstantinou et al, 1995;Fisher et al, 1998). It may be postulated that the effect of amantadine may occur by at least two different mechanisms: increasing availability of DA, and low affinity uncompetitive blocking of NMDA-type glutamate receptors.…”

“…Amantadine is efficacious as a monotherapy and also exhibits a synergistic effect with levodopa and anticholinergics. It has been known for quite a number of years that the administration of amantadine to small rodents releases dopamine (DA) from striatal slices (Scatton et al, 1970), increases the brain DA outflow (von Voigtlander and Moore, 1970), and produces a low-affinity uncompetitive blockade of the n-methyl-D-aspartic acid (NMDA) receptor (Danysz et al, 1994).…”