Modifications of the behavioral profile of non-competitive NMDA receptor antagonists, memantine, amantadine and (+)MK-801 after chronic administration

Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists show antip arkinsonian-like activity in animal models, and possess neuroprotective pro perties. However they also induce a number of behavioral side effects in ro dents at higher doses; these include learning impairment, hyperlocomotion, and ataxia. The present study focused on the possible development of tolera nce, or sensitization, to any of these effects after sustained administrati on, either by repeated injection or continuous infusion. When memantine or (+)MK-801 (20 and 0.31 mg/kg/day respectively) were either infused or repea tedly injected for 14 days, tolerance was observed to their learning impair ing effect at high doses, in a passive avoidance test. Tolerance to their a taxic effect developed after repeated administration ((+)MK-801 and memanti ne), or after infusion (memantine). Sensitization to the locomotor stimulat ion was seen following repetitive injections of memantine for 14 days, but not seen with (+)MK-801. In animals with an unilateral 6-OHDA lesion of the nigrostriatal system, acute administration of memantine caused ipsilateral rotations, which were augmented following 14 days of infusion. The potency of amantadine to antagonize neuroleptic-induced catalepsy was unchanged fo llowing either infusion or repeated injections. The various acute effects o f non-competitive NMDA receptor antagonists were modified differently by su stained treatment (i.e. tolerance to learning impairment and ataxia; sensit ization to memantine's locomotor stimulation). The anti-cataleptic activity of amantadine remained unaltered. However, differences between drugs and t he two treatment regimens (i.e. repetitive versus continuous treatments) we re apparent. (C) 1999 Lippincott Williams & Wilkins.