INVESTIGATIONS ON THE MECHANISM OF TETRAHYDRO-9-AMINOACRIDINE-INDUCEDPRESYNAPTIC INHIBITION IN THE RAT AMYGDALA

Tetrahydro-9-aminoacridine, a centrally acting anticholinesterase, has been reported to improve clinical conditions of certain patients with Alzheimer's disease. A previous study from our laboratory suggested t hat tetrahydro-9-aminoacridine presynaptically inhibited synaptic tran smission. In the present study, the mechanism responsible for presynap tic inhibition mediated by tetrahydro-9-aminoacridine was studied in t he rat amygdalar slice preparation using intracellular recording techn iques. Bath application of tetrahydro-9-aminoacridine reversibly suppr essed the excitatory postsynaptic potential. Tetrahydro-9-aminoacridin e's inhibitory action was unaffected by the pretreatment of slices wit h baclofen (5 mu M), suggesting that it did not act by eliciting the r elease of GABA, which binds presynaptic GABA(B) receptors to inhibit g lutamate release. The synaptic depressant effect of tetrahydro-9-amino acridine was blocked in the presence of 4-aminopyridine, The action of 4-aminopyridine could be reversed by reducing extracellular Ca2+ conc entrations from a control level of 2.5 to 0.5 mM, suggesting that tetr ahydro-9-aminoacridine inhibits excitatory postsynaptic potentials by acting directly at the terminals to decrease a Ca2+ influx. The L-type Ca2+ channel blocker nifedipine (50 mu M) had no effect on tetrahydro -9-aminoacridine-induced presynaptic inhibition. However, the depressa nt effect of tetrahydro-9-aminoacridine was partially occluded in slic es pretreated with the N-type Ca2+ channel blocker omega-conotoxin GVI A (1 mu M). It is concluded that a reduction in omega-conotoxin GVIA-s ensitive Ca2+ currents contributes to tetrahydro-9-aminoacridine-media ted presynaptic inhibition. After exposure to bicuculline, a GABA(A) r eceptor antagonist, afferent stimulation evoked epileptiform bursts. O ccasionally, spontaneous bursts similar in waveform to synaptically tr iggered bursts also occurred in disinhibited slices. Application of te trahydro-9-aminoacridine reversibly reduced the burst duration in a co ncentration-dependent manner. These results suggest that tetrahydro-9- aminoacridine possesses anticonvulsant activity against disinhibited b ursts.