Microionophoretic study with milacemide, a glycine precursor, on mammalian central nervous system cells.
1. The effect of milacemide, a glycine percursor known to increase gamma-aminobutyric acid (GABA) and glycine content in the brain, and to have anticonvulsant properties, was tested by ionophoresis on 247 neurones situated in the cerebral cortex and in deeper structures of cats and rats anaesthetized with urethane. 2. Virtually all the neurones, either firing spontaneously or exogenously driven by the excitatory amino acids, glutamate, N-methyl-D-aspartate (NMDA), kainate and quisqualate or by acetylcholine, were reversibly depressed in a dose-dependent fashion. The same depressant effect was observed in animals pretreated with the monoamine oxidase B inhibitor (IMAO-B) deprenyl which is known to reduce milacemide metabolism into glycinamide and glycine. Intravenous administration of milacemide (10 to 100 mg kg-1) also depressed the firing induced by glutamate, NMDA and acetylcholine. 3. When compared to GABA, milacemide was a weaker depressant. However, its effect could still be observed in the presence of the reversible GABAA antagonist, SR 95531, and thus milacemide is unlikely to act through GABA receptors. In addition, on cells unaffected by glycine, milacemide also had a depressant effect, and on cells inhibited by glycine, it was still capable of depressing cell firing during reversible blockade by strychnine of the glycine inhibitory action; thus milacemide is unlikely to act through glycine receptors. Simultaneous release of milacemide and GABA or of milacemide and glycine, did not show potentiation of the inhibitory amino acid action. However, the depressant effect of milacemide was additive with that of GABA and glycine. 4. No consistent depression of glutamate-induced firing was obtained by ionophoresis of glycinamide, the first metabolite of milacemide. 5. It is concluded that milacemide by itself is a depressant agent and that its depressant effect does not necessarily require its metabolism into glycine, or its stimulator effect on the production of GABA.
Godfraind
J M
JM
Laboratoire de Neurophysiologie, Faculté de Médecine UCL, Université de Louvain en Woluwé, Bruxelles, Belgium.
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002415:Cats; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007478:Iontophoresis; D007608:Kainic Acid / Q000494:pharmacology; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects; D010069:Oxadiazoles / Q000494:pharmacology; D016318:Quisqualic Acid; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000081:Acetamides; D008996:Monoamine Oxidase Inhibitors; D010069:Oxadiazoles; C039332:milacemide; D001224:Aspartic Acid; C018556:glycine amide; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D007608:Kainic Acid; D005998:Glycine