Inhibitory effects of the antiparkinsonian drugs memantine and amantadine on N-methyl-D-aspartate-evoked acetylcholine release in the rabbit caudate nucleus in vitro.
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.
Neuropharmakologisches Labor, Neurologischen Universitätsklinik, Freiburg, Federal Republic of Germany.
A
A
Lupp
C H
CH
Lücking
R
R
Koch
R
R
Jackisch
T J
TJ
Feuerstein
D000109:Acetylcholine / Q000378:metabolism*; D000547:Amantadine / Q000494:pharmacology*; D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D011817:Rabbits; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology; D014316:Tritium
D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D018698:Glutamic Acid; D013779:Tetrodotoxin; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D000547:Amantadine; D008274:Magnesium; D000109:Acetylcholine; D004298:Dopamine; D008559:Memantine