[Ketamine inhibits n-methyl-d-aspartate (NMDA) receptor mediated acetylcholine release from rabbit caudate nucleus slices].

Slices of the rabbit caudate nucleus were incubated with [3H]choline for 30 min and then superfused continuously with Mg(2+)-free medium at 37 degrees C. Stimulation with N-methyl-D-aspartate (NMDA) caused a concentration-dependent release of [3H]acetylcholine (ACh), which was abolished in the presence of MG2+. This release of ACh was exocytotic and mediated by action potentials. NMDA channel antagonists inhibited the NMDA-evoked [3H]ACh release in a use-dependent manner, with the following rank order of potency: dizolcipine [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclo-hepten-5,10-imine maleate; MK-801] > (+)ketamine = (+/-)ketamine < (-)ketamine > memantine > amantadine. Also, AP-5 [(+/-)-2-amino-5-phosphopentanoic acid] depressed the NMDA-induced release of [3H]ACh, acting, however, in a competitive manner. At the neuropathologic level, Parkinson's disease is characterized by an overshoot of striatal cholinergic transmission due to the decreased inhibitory dopaminergic input from the substantia nigra. The well-known antiparkinsonian effect of memantine and amantadine is most probably due to a blockade of NMDA-receptor-linked ion channels on striatal cholinergic interneurons, leading in turn to a diminished release of ACh. Since ketamine diminished cholinergic neurotransmission to a similar degree to that achieved with memantine and amantadine and even more potently than the adamantanes, and that at concentrations far below those needed for its anaesthetic and analgesic properties, it seems worthwhile to test this drug as an antiparkinsonian agent clinically.