CM 54903, a new psychotropic drug with a particular pharmacological profile produced a widespread but short-lasting decrease in acetylcholine content in rat brain hemispheric regions but not in the midbrain-hindbrain or cerebellum at the dose of 40 mg/kg, i.p. The decrease was most conspicuous in the striatum. Brain regional choline contents were unaltered as were the acetylcholine turnover rates in the striatum and hippocampus. Neither choline acetyltransferase nor acetylcholinesterase activities were altered after the in vitro incubation or the in vivo administration of high amounts of the drug. CM 54903 was found to be a competitive, reversible inhibitor of the sodium-dependent high affinity uptake of choline by crude hippocampal and striatal synaptosomal preparations showing an IC50 of 10 μM in vitro. Despite the fact that the drug readily crosses the blood-brain barrier and achieves brain concentrations several-fold greater than its in vitro IC50, CM 54903 did not inhibit choline uptake in vivo although it was capable of preventing the pentylenetetrazol-stimulated choline uptake by hippocampal synaptosomes. The changes in striatal acetylcholine content induced by the blockade or the stimulation of muscarinic cholinergic receptors or dopaminergic receptors did not interfere with the effect of CM 54903 on striatal acetylcholine content while pentylenetetrazol completely prevented the decrease. The results taken together indicate that the major effect of CM 54903 on the cholinergic neurons is at the presynaptic level to compete with choline at its uptake sites.
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