INCREASE OF ACETYLCHOLINE-RELEASE BY NEBRACETAM IN DOG CARDIAC SYMPATHETIC-GANGLION

The effects of nebracetam (4-aminomethyl-1-benzylpyrrolidine-2-one hemifumarate, WEB 1881FU), a potential cognitive enhancer, on acetylcholine release from the preganglionic nerve terminals were investigated in the isolated dog stellate ganglia. Acetylcholine release from the isolated ganglia by preganglionic stimulation (5 Hz) was enhanced in the presence of nebracetam, 10(-7) to 10(-5) M. The release was decreased to a certain extent by bethanechol, 10(-5) M, and this decrease was completely antagonized by AFDX-116 (10(-5) M), a selective M(2) muscarinic antagonist, but was unaffected by nebracetam (10(-6) M). Under the depleted condition of acetylcholine induced by pretreatment with hemicholinium-3 (10(-5) M) in combination with prolonged preganglionic stimulation, the release was increased to a degree by nebracetam or choline alone and was markedly increased in the presence of both nebracetam and choline. Nebracetam did not directly act on choline acetyltransferase activity, but acetylcholine formation was stimulated in the isolated ganglion incubated with the agent at 10(-6) M and in the ganglion isolated from the dog to which nebracetam, 5 mg/kg, was previously administered i.v. Uptake of choline in the isolated ganglia was not altered by nebracetam (10(-6) M) but was enhanced under the depleted conditions. These findings suggest that nebracetam enhances acetylcholine release from presynaptic sites of dog stellate ganglia not by blocking presynaptic M(2) muscarinic autoreceptors but by accelerating acetylcholine formation, and by increasing choline uptake when acetylcholine is depleted.