Investigations on the mechanism of tetrahydro-9-aminoacridine-induced presynaptic 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 that tetrahydro-9-aminoacridine presynaptically inhibited synaptic transmission. In the present study, the mechanism responsible for presynaptic inhibition mediated by tetrahydro-9-aminoacridine was studied in the rat amygdalar slice preparation using intracellular recording techniques. Bath application of tetrahydro-9-aminoacridine reversibly suppressed the excitatory postsynaptic potential. Tetrahydro-9-aminoacridine's inhibitory action was unaffected by the pretreatment of slices with baclofen (5 microM), suggesting that it did not act by eliciting the release of GABA, which binds presynaptic GABAB receptors to inhibit glutamate release. The synaptic depressant effect of tetrahydro-9-aminoacridine was blocked in the presence of 4-aminopyridine. The action of 4-aminopyridine could be reversed by reducing extracellular Ca2+ concentrations from a control level of 2.5 to 0.5 mM, suggesting that tetrahydro-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 microM) had no effect on tetrahydro-9-aminoacridine-induced presynaptic inhibition. However, the depressant effect of tetrahydro-9-aminoacridine was partially occluded in slices pretreated with the N-type Ca2+ channel blocker omega-conotoxin GVIA (1 microM). It is concluded that a reduction in omega-conotoxin GVIA-sensitive Ca2+ currents contributes to tetrahydro-9-aminoacridine-mediated presynaptic inhibition. After exposure to bicuculline, a GABAA receptor antagonist, afferent stimulation evoked epileptiform bursts. Occasionally, spontaneous bursts similar in waveform to synaptically triggered bursts also occurred in disinhibited slices. Application of tetrahydro-9-aminoacridine reversibly reduced the burst duration in a concentration-dependent manner. These results suggest that tetrahydro-9-aminoacridine possesses anticonvulsant activity against disinhibited bursts.
Wang
S J
SJ
Department of Pharmacology, National Cheng-Kung University, Tainan City, Taiwan.
Huang
C C
CC
Gean
P W
PW
D015761:4-Aminopyridine / Q000494:pharmacology; D000544:Alzheimer Disease / Q000188:drug therapy; D000679:Amygdala / Q000187:drug effects*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects*; D013619:Tacrine / Q000494:pharmacology*; D013997:Time Factors
D013619:Tacrine; D015761:4-Aminopyridine; D001418:Baclofen; D009543:Nifedipine