Effects of the centrally acting cholinesterase inhibitors tetrahydroaminoacridine and E2020 on the basal concentration of extracellular acetylcholine in the hippocampus of freely moving rats.
The effects of the centrally acting cholinesterase (ChE) inhibitors, tetrahydroaminoacridine (THA) and E2020 (1-benzyl-4-[(5,6-dimethoxy-1-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 mumol/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.(ABSTRACT TRUNCATED AT 250 WORDS)
Kawashima
K
K
Department of Pharmacology, Kyoritsu College of Pharmacy, Tokyo, Japan.
Sato
A
A
Yoshizawa
M
M
Fujii
T
T
Fujimoto
K
K
Suzuki
T
T
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D006624:Hippocampus / Q000187:drug effects*; D007189:Indans / Q000494:pharmacology; D008297:Male; D009068:Movement; D010830:Physostigmine / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D013619:Tacrine / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D013619:Tacrine; D000077265:Donepezil; D010830:Physostigmine; D000109:Acetylcholine