Effects of the centrally acting cholinesterase inhibitors tetrahydroaminoacridine and E2020 on the basal concentration of extracellular acetylcholine in the hippocampus of freely moving rats

Koichiro Kawashima, Akio Sato, Masayuki Yoshizawa, Takeshi Fujii, Kazuko Fujimoto, Takeshi Suzuki

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Abstract

The effects of the centrally acting cholinesterase (ChE) inhibitors, tetrahydroaminoacridine (THA) and E2020 (1-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl] methylpiperidine hydrochloride), potential drugs for the treatment of senile dementia, on the basal extracellular acetylcholine (ACh) concentration in the hippocampus of freely moving rats, were determined using a microdialysis technique without the use of a ChE inhibitor in the perfusion fluid and a sensitive RIA. The mean (±SEM) basal ACh content in the perfusate was 103.1 ± 3.6 fmol/sample collected over 30 min when microdialysis probes with a length of 3 mm dialysis membrane were used. The content of ACh decreased to an almost undetectable level upon perfusion of magnesium, suggesting that, in the present study, most of the ACh detected in the perfusates was due to cholinergic neuronal activity. THA (1.65 mg/kg, i.p.) produced an insignificant increase in the extracellular ACh concentration, but a dose of 5 mg/kg, i.p. caused a prolonged and significant 5.5-fold increase from the control value. E2020 (0.65 and 2 mg/kg, i.p.) produced significant, prolonged and dose-dependent increases (4 and 12 times the control value, respectively), the peak effect occurring within 1 h. Perfusion with 10 μmol/l physostigmine produced an about 30-fold increase of ACh output, suggesting that the basal extracellular ACh concentration is highly dependent on ChE activity. When ChE was inhibited locally by perfusion with physostigmine, THA (5 mg/kg) produced a transient and, at its maximum, a 1.42-fold increase in extracellular ACh concentration. These results demonstrate that the basal, physiological, extracellular ACh concentration in the hippocampus of freely moving rats can be determined using a microdialysis technique and a sensitive RIA, and suggest that THA and E 2020 increase ACh concentration in the synaptic cleft of the hippocampus in a dose-dependent manner mostly through ChE inhibition.

Original languageEnglish
Pages (from-to)523-528
Number of pages6
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume350
Issue number5
DOIs
Publication statusPublished - 1994 Nov

Fingerprint

Tacrine
Cholinesterase Inhibitors
Acetylcholine
Hippocampus
Cholinesterases
Microdialysis
Perfusion
Physostigmine
donepezil
Magnesium
Cholinergic Agents
Dialysis
Alzheimer Disease

Keywords

  • Acetylcholine
  • E2020
  • Hippocampus
  • Microdialysis
  • Physostigmine
  • RIA
  • Tetrahydroaminoacridine

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Effects of the centrally acting cholinesterase inhibitors tetrahydroaminoacridine and E2020 on the basal concentration of extracellular acetylcholine in the hippocampus of freely moving rats",
abstract = "The effects of the centrally acting cholinesterase (ChE) inhibitors, tetrahydroaminoacridine (THA) and E2020 (1-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl] methylpiperidine hydrochloride), potential drugs for the treatment of senile dementia, on the basal extracellular acetylcholine (ACh) concentration in the hippocampus of freely moving rats, were determined using a microdialysis technique without the use of a ChE inhibitor in the perfusion fluid and a sensitive RIA. The mean (±SEM) basal ACh content in the perfusate was 103.1 ± 3.6 fmol/sample collected over 30 min when microdialysis probes with a length of 3 mm dialysis membrane were used. The content of ACh decreased to an almost undetectable level upon perfusion of magnesium, suggesting that, in the present study, most of the ACh detected in the perfusates was due to cholinergic neuronal activity. THA (1.65 mg/kg, i.p.) produced an insignificant increase in the extracellular ACh concentration, but a dose of 5 mg/kg, i.p. caused a prolonged and significant 5.5-fold increase from the control value. E2020 (0.65 and 2 mg/kg, i.p.) produced significant, prolonged and dose-dependent increases (4 and 12 times the control value, respectively), the peak effect occurring within 1 h. Perfusion with 10 μmol/l physostigmine produced an about 30-fold increase of ACh output, suggesting that the basal extracellular ACh concentration is highly dependent on ChE activity. When ChE was inhibited locally by perfusion with physostigmine, THA (5 mg/kg) produced a transient and, at its maximum, a 1.42-fold increase in extracellular ACh concentration. These results demonstrate that the basal, physiological, extracellular ACh concentration in the hippocampus of freely moving rats can be determined using a microdialysis technique and a sensitive RIA, and suggest that THA and E 2020 increase ACh concentration in the synaptic cleft of the hippocampus in a dose-dependent manner mostly through ChE inhibition.",
keywords = "Acetylcholine, E2020, Hippocampus, Microdialysis, Physostigmine, RIA, Tetrahydroaminoacridine",
author = "Koichiro Kawashima and Akio Sato and Masayuki Yoshizawa and Takeshi Fujii and Kazuko Fujimoto and Takeshi Suzuki",
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T1 - Effects of the centrally acting cholinesterase inhibitors tetrahydroaminoacridine and E2020 on the basal concentration of extracellular acetylcholine in the hippocampus of freely moving rats

AU - Kawashima, Koichiro

AU - Sato, Akio

AU - Yoshizawa, Masayuki

AU - Fujii, Takeshi

AU - Fujimoto, Kazuko

AU - Suzuki, Takeshi

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N2 - The effects of the centrally acting cholinesterase (ChE) inhibitors, tetrahydroaminoacridine (THA) and E2020 (1-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl] methylpiperidine hydrochloride), potential drugs for the treatment of senile dementia, on the basal extracellular acetylcholine (ACh) concentration in the hippocampus of freely moving rats, were determined using a microdialysis technique without the use of a ChE inhibitor in the perfusion fluid and a sensitive RIA. The mean (±SEM) basal ACh content in the perfusate was 103.1 ± 3.6 fmol/sample collected over 30 min when microdialysis probes with a length of 3 mm dialysis membrane were used. The content of ACh decreased to an almost undetectable level upon perfusion of magnesium, suggesting that, in the present study, most of the ACh detected in the perfusates was due to cholinergic neuronal activity. THA (1.65 mg/kg, i.p.) produced an insignificant increase in the extracellular ACh concentration, but a dose of 5 mg/kg, i.p. caused a prolonged and significant 5.5-fold increase from the control value. E2020 (0.65 and 2 mg/kg, i.p.) produced significant, prolonged and dose-dependent increases (4 and 12 times the control value, respectively), the peak effect occurring within 1 h. Perfusion with 10 μmol/l physostigmine produced an about 30-fold increase of ACh output, suggesting that the basal extracellular ACh concentration is highly dependent on ChE activity. When ChE was inhibited locally by perfusion with physostigmine, THA (5 mg/kg) produced a transient and, at its maximum, a 1.42-fold increase in extracellular ACh concentration. These results demonstrate that the basal, physiological, extracellular ACh concentration in the hippocampus of freely moving rats can be determined using a microdialysis technique and a sensitive RIA, and suggest that THA and E 2020 increase ACh concentration in the synaptic cleft of the hippocampus in a dose-dependent manner mostly through ChE inhibition.

AB - The effects of the centrally acting cholinesterase (ChE) inhibitors, tetrahydroaminoacridine (THA) and E2020 (1-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl] methylpiperidine hydrochloride), potential drugs for the treatment of senile dementia, on the basal extracellular acetylcholine (ACh) concentration in the hippocampus of freely moving rats, were determined using a microdialysis technique without the use of a ChE inhibitor in the perfusion fluid and a sensitive RIA. The mean (±SEM) basal ACh content in the perfusate was 103.1 ± 3.6 fmol/sample collected over 30 min when microdialysis probes with a length of 3 mm dialysis membrane were used. The content of ACh decreased to an almost undetectable level upon perfusion of magnesium, suggesting that, in the present study, most of the ACh detected in the perfusates was due to cholinergic neuronal activity. THA (1.65 mg/kg, i.p.) produced an insignificant increase in the extracellular ACh concentration, but a dose of 5 mg/kg, i.p. caused a prolonged and significant 5.5-fold increase from the control value. E2020 (0.65 and 2 mg/kg, i.p.) produced significant, prolonged and dose-dependent increases (4 and 12 times the control value, respectively), the peak effect occurring within 1 h. Perfusion with 10 μmol/l physostigmine produced an about 30-fold increase of ACh output, suggesting that the basal extracellular ACh concentration is highly dependent on ChE activity. When ChE was inhibited locally by perfusion with physostigmine, THA (5 mg/kg) produced a transient and, at its maximum, a 1.42-fold increase in extracellular ACh concentration. These results demonstrate that the basal, physiological, extracellular ACh concentration in the hippocampus of freely moving rats can be determined using a microdialysis technique and a sensitive RIA, and suggest that THA and E 2020 increase ACh concentration in the synaptic cleft of the hippocampus in a dose-dependent manner mostly through ChE inhibition.

KW - Acetylcholine

KW - E2020

KW - Hippocampus

KW - Microdialysis

KW - Physostigmine

KW - RIA

KW - Tetrahydroaminoacridine

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