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-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)

Estimation of Plasma IC50 of Donepezil Hydrochloride for Brain Acetylcholinesterase Inhibition in Monkey Using N-[11C]methylpiperidin-4-yl Acetate ([11C]MP4A) and PET

“…This mechanism of action has been experimentally confirmed in rats (Kawashima et al, 1994;Kosasa et al, 1999) and monkeys (Tsukada et al, 2004), as measured qualitatively by microdialysis. Since [ 11 C]MP4A is a substrate-type radiotracer, the increase in synaptic acetylcholine levels would affect k 3 of [ 11 C]MP4A through two mechanisms as follows.…”

“…Furthermore, using microdialysis, it is reported that donepezil dose-dependently increases the extracellular acetylcholine concentration in rats (Kawashima et al, 1994;Kosasa et al, 1999) and in monkey (Tsukada et al, 2004), which may cause additional AChE inhibition (substrate inhibition) (Reiner and Radic, 2000). With positron emission tomography (PET), not only can we assess brain AChE inhibition by a reversible inhibitor without tissue-dilution effect, but also we can evaluate the inhibitory effects of increased synaptic acetylcholine levels on AChE in vivo.…”

Selective 5-HT1A Antagonists WAY 100635 and NAD-299 Attenuate the Impairment of Passive Avoidance Caused by Scopolamine in the Rat

“…It is generally believed that AChE inhibitors such as physostigmine act by increasing synaptic ACh (Kawashima et al, 1994;Scali et al, 1997), resulting in competition with scopolamine at the postsynaptic muscarinic receptors. In agreement with this view, tacrine and donepezil attenuated or completely blocked the inhibitory effects of scopolamine depending on the dose of the muscarinic receptor antagonist.…”

Donepezil for Alzheimer's Disease: Pharmacodynamic, Pharmacokinetic, and Clinical Profiles

“…After donepezil, 0.5 and 2.0 mg/kg s.c. the ACh levels were at 30 min twice and at 1 h 21 times the control value (24). After donepezil at 0.65 and 2 mg/kg i.p., the increase was 4 and 12 times, respectively, the peak effect occurred within 1 h (37). In this respect donepezil was more potent than tacrine (37).…”

“…Donepezil increased extracellular ACh levels in the hippocampus and cortex of rats (24,37). After donepezil, 0.5 and 2.0 mg/kg s.c. the ACh levels were at 30 min twice and at 1 h 21 times the control value (24).…”