Investigations on the mechanism of tetrahydro-9-aminoacridine-induced presynaptic inhibition in the rat amygdala

S. J. Wang, C. C. Huang, Po-Wu Gean

Research output: Contribution to journalArticle

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Abstract

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 ìM), 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 μM) 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 ω-conotoxin GVIA (1 μM). It is concluded that a reduction in ω-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.

Original languageEnglish
Pages (from-to)409-415
Number of pages7
JournalNeuroscience
Volume70
Issue number2
DOIs
Publication statusPublished - 1996 Jan 1

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Aminacrine
Amygdala
4-Aminopyridine
Excitatory Postsynaptic Potentials
Inhibition (Psychology)
Conotoxins
Presynaptic Receptors
GABA-A Receptor Antagonists
Baclofen
Bicuculline
Cholinesterase Inhibitors
Nifedipine
Baths
Synaptic Transmission
Anticonvulsants
gamma-Aminobutyric Acid

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

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title = "Investigations on the mechanism of tetrahydro-9-aminoacridine-induced presynaptic inhibition in the rat amygdala",
abstract = "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 {\`i}M), 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 μM) 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 ω-conotoxin GVIA (1 μM). It is concluded that a reduction in ω-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.",
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Investigations on the mechanism of tetrahydro-9-aminoacridine-induced presynaptic inhibition in the rat amygdala. / Wang, S. J.; Huang, C. C.; Gean, Po-Wu.

In: Neuroscience, Vol. 70, No. 2, 01.01.1996, p. 409-415.

Research output: Contribution to journalArticle

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N2 - 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 ìM), 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 μM) 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 ω-conotoxin GVIA (1 μM). It is concluded that a reduction in ω-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.

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