TY - JOUR T1 - Inhibitory effects of the antiparkinsonian drugs memantine and amantadine on N-methyl-D-aspartate-evoked acetylcholine release in the rabbit caudate nucleus in vitro. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 717 LP - 724 VL - 263 IS - 2 AU - A Lupp AU - C H Lücking AU - R Koch AU - R Jackisch AU - T J Feuerstein Y1 - 1992/11/01 UR - http://jpet.aspetjournals.org/content/263/2/717.abstract N2 - Slices of the rabbit caudate nucleus were incubated with [3H]choline or [3H]dopamine and then superfused continuously with Mg(++)-free medium. Stimulation with N-methyl-D-aspartate (NMDA), alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA), L-glutamate and kainic acid (in that rank order of potencies) caused a concentration-dependent increase in [3H]ACh efflux, which was abolished in the presence of Mg++. This kind of release was Ca(++)-dependent and tetrodotoxin-sensitive. In contrast, NMDA was hardly effective in stimulating [3H]ACh release from hippocampal or cortical slices, as well as [3H]dopamine release from slices of rabbit caudate nucleus. Hence, the presence of cell bodies of stimulated neurons seems to be a prerequisite for the induction of release via NMDA receptors. Dizocilpine [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate] at nanomolar concentrations, as well as memantine and amantadine at low micromolar concentrations, inhibited the L-glutamate- and NMDA-evoked [3H]ACh release in a concentration-dependent, noncompetitive and use-dependent manner. Also (+/-)-2-amino-5-phosphopentanoic acid at micromolar concentrations depressed the L-glutamate- and NMDA-induced release, acting, however, in a competitive manner. It is concluded that, by antagonizing NMDA receptor-mediated ACh release, memantine and amantadine may act as functional "anticholinergics" when administered clinically to treat Parkinson's disease. ER -