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

• Published in: British journal of pharmacology Vol. 98; no. 4; pp. 1127 - 1136
• Main Authors: Robinson, T.N., Souza, R.J., Cross, A.J., Green, A.R.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-12-1989; Nature Publishing
• Subjects: Aminoacridines - pharmacology; Animals; Biogenic Monoamines - metabolism; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cholinergic system; Chromatography, High Pressure Liquid; Dopamine - metabolism; Fenfluramine - pharmacology; In Vitro Techniques; Male; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Parasympathomimetics - pharmacology; Pargyline - pharmacology; Pharmacology. Drug treatments; Potassium Channels - drug effects; Rats; Serotonin - metabolism; Tacrine - pharmacology; Brain; Dopamine; Rat; Serotonin; Rodentia; Central nervous system; Enzyme inhibitor; Acetylcholinesterase; In vitro; Biological activity; Tissue; Vertebrata; Mammalia; Animal; Biogenic amine; Neurotransmitter; Mechanism of action; Release
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1989.tb12656.x

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 (100 μm)‐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 10 μm) 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 (5 mg kg−1, 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 (IC50 = 0.036 μm), imipramine (IC50 = 0.20 μm) and THA (IC50 = 19.9 μm) 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 (5 μm) 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.