The cholinergic pharmacology of tetrahydroaminoacridine <i>in vivo</i> and <i>in vitro</i>

Hunter, A. J.; Murray, Tracey K.; Jones, Jeffrey A.; Cross, A.J.; Green, A.R.

doi:10.1111/j.1476-5381.1989.tb16865.x

Cited by 75 publications

(48 citation statements)

References 19 publications

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“…It has also been reported that nicotine will stimulate striatal 5-HT release (Westfall et al, 1983). In addition to its inhibitory activity against AChE (Shaw & Bentley, 1953;Steinberg et al, 1975) THA is centrally active at both muscarinic and, more weakly, at nicotinic receptors (Nilsson et al, 1987;Hunter et al, 1989;Perry et al, 1988;Pearce & Potter, 1988). It was feasible therefore that THA might modulate monoamine release via ACh receptors, either through a direct action or by increasing the concentration of ACh.…”

Section: Effect Of Tha On S-ht Reuptakementioning

confidence: 99%

The mechanism of tetrahydroaminoacridine‐evoked release of endogenous 5‐hydroxytryptamine and dopamine from rat brain tissue prisms

Robinson¹,

Souza²,

Cross³

et al. 1989

British J Pharmacology

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1 Tetrahydroaminoacridine (THA) is an acetylcholinesterase (AChE) inhibitor which may have a greater therapeutic effect in Alzheimer-type dementia (ATD) than other cholinergic agents. This suggests possible non-cholinergic properties. We have therefore studied the effects of THA on the release of endogenous 5-hydroxytryptamine (5-HT) from rat cortical prisms and dopamine from striatal prisms. 2 In the presence of K+ (1 mM), THA stimulated release of both 5-HT and dopamine. THA (100pM)-evoked monoamine release was comparable, but not additive with the release produced by K+ (35 mM). The effect was not maximal at 1 mm THA. THA-evoked release of 5-HT was independent of the presence of Ca2 + in the external medium.3 Drugs acting on the cholinergic system, nicotine, mecamylamine, atropine, oxotremorine, physostigmine and neostigmine (all 10pM) had no effect on 5-HT and dopamine release. 4-Aminopyridine (4-AP), a potent acetylcholine-releasing agent, had no effect on 5-HT release and was approximately 100 fold less active than THA on dopamine release. 4 Both THA and reserpine enhanced the release of 5-HT in the presence of the monoamine oxidase inhibitor, pargyline. Reserpine-but not THA-evoked release was abolished in the absence of pargyline. Reserpine (5mg kg -', i.p.) markedly depleted brain monoamine concentrations 3 h after injection, while THA (15 mg kg-1, i.p.) had no effect. 5 Chloroamphetamine and fenfluramine both released 5-HT in a Ca2+-independent manner and with a similar potency to THA, while (+)-amphetamine released dopamine with a similar potency to THA. The effects of the amphetamines were not maximal at 1 mm. However, unlike THA, chloroamphetamine-evoked release of 5-HT was additive with release evoked by K+ (35 mM).6 Clomipramine (IC5o = 0.036upM), imipramine (IC50 = 0.20 pM) and THA (IC50 = 19.9 pM) all inhibited the uptake of [3H]-5-HT into a P2 membrane preparation. However, none of these compounds inhibited [3H]-5-HT uptake into tissue prisms during the release experiments in which the reuptake inhibitor fluoxetine (5puM) was present. 7 We conclude that THA does not release endogenous 5-HT through a cholinergic, reserpine-or amphetamine-like mechanism or through inhibition of reuptake. The possibility exists that the release may occur via blockade of 4-AP-insensitive K+ channels.

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Section: Effect Of Tha On S-ht Reuptakementioning

confidence: 99%

The mechanism of tetrahydroaminoacridine‐evoked release of endogenous 5‐hydroxytryptamine and dopamine from rat brain tissue prisms

Robinson¹,

Souza²,

Cross³

et al. 1989

British J Pharmacology

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“…In the case of reversible cholinesterase inhibitors such as tacrine and donepezil, inhibition of enzyme activity can be partially reversed by dilution, because of dissociation of the inhibitor from the enzyme with time (Hunter et al, 1989;Dawson, 1990;Kosasa et al, 2000). 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).…”

Section: Introductionmentioning

confidence: 99%

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

Shiraishi

Kikuchi

Fukushi

et al. 2005

Neuropsychopharmacol

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Donepezil hydrochloride is a potent and selective inhibitor for brain acetylcholinesterase (AChE) and is currently used worldwide for the treatment of Alzheimer's disease. Until now, there is no in vivo study on the relation between the plasma concentration and the brain AChE inhibition. The purpose of this study was to estimate in vivo plasma IC 50 of donepezil in living monkeys by measuring plasma donepezil concentration (LC/MS/MS) and brain AChE activity with positron emission tomography (PET) and N-[ 11 C]methylpiperidin-4-yl acetate, which is an acetylcholine analog recently developed by us for quantifying in vivo brain AChE activity. PET scans with donepezil at two doses, 100 mg/kg (donepezil-1; N ¼ 5) or 250 mg/kg (donepezil-2; N ¼ 5), were performed using the same monkeys at 4-week intervals. Before each PET scan, baseline PET scans (N ¼ 10 in total) were performed without donepezil. The plasma donepezil concentrations 14 min after intravenous injection were proportional to the doses, 17.272.9 ng/ml (donepezil-1) and 44.075.0 ng/ml (donepezil-2), and the mean AChE inhibitions in four neocortical regions as evaluated by PET were also dose-dependent, 27% (donepezil-1) and 53% (donepezil-2). In IC 50 estimation, measured plasma donepezil concentrations were corrected for the change during PET scan. The IC 50 values (estimate7SE) were 4279.0 (ng/ml; donepezil-1), 3473.2 (donepezil-2), and 3774.1 (combined data). The present method may be useful for in vivo evaluation of other AChE inhibitors and novel drugs.

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“…The drug exerts diverse effects [3,4]. Some of them are not related to the cholinergic system [5,6] and may underlie various side effects. Tacrine molecule freely penetrates through cell membranes [7].…”

Section: Introductionmentioning

confidence: 99%

Participation of cAMP in tacrine-induced gastric smooth muscle relaxation

et al. 2010

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Tacrine, a well-known acetylcholinesterase inhibitor, applied in concentrations higher than 2×10-5 mol/l promoted Ca 2+ -independent relaxation of rat gastric smooth muscles in experiments in vitro. The relaxation was not cholinergic and was a result of influence of tacrine over intracellular signaling pathways regulating smooth muscle contraction/relaxation. The nature of this untypical muscle relaxation was studied by using smooth muscle strips isolated from rat stomach. Their bioelectrical and mechanical responses were recorded after treatment with tacrine and different activators or blockers of intracellular pathways involved in muscle contractility. Following the activation of adenylate cyclase with 1×10 -6 mol/l forskolin and increase in the concentration of cyclic adenosine monophosphate (cAMP) after application of 4×10 -5 mol/l SQ22536, a significant decrease in the muscle relaxation was observed. Theophylline (2×10 -4 mol/l), a phosphodiesterase inhibitor, had no effect on the amplitude of tacrine-induced relaxation. The latter was also reduced by inhibition of protein kinase A (PKA) with 5×10 -6 mol/l KT5720. These findings support the assumption that tacrine promoted smooth muscle relaxation through PKA-induced phosphorylation and inhibition of myosin light chain kinase activity. The reduction of spike-linked Ca 2+ influx provoked by tacrine was probably a secondary contributing process, associated with an influence of increased cAMP level on Ca 2+ channels.

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The cholinergic pharmacology of tetrahydroaminoacridine in vivo and in vitro

Cited by 75 publications

References 19 publications

The mechanism of tetrahydroaminoacridine‐evoked release of endogenous 5‐hydroxytryptamine and dopamine from rat brain tissue prisms

The mechanism of tetrahydroaminoacridine‐evoked release of endogenous 5‐hydroxytryptamine and dopamine from rat brain tissue prisms

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

Participation of cAMP in tacrine-induced gastric smooth muscle relaxation

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