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

Abstract

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.

Nicotinic acetylcholine receptor (nACh-R) agonist-induced changes in brain monoamine turnover in mice

“…The doses of THA used in this experiment are sufficient to produce a cognitive-enhancing effect in an animal model (Hagan et al 1989). The increase in brain NA, DA and 5-HT turnover produced by THA in the present study is consistent with previous studies that demonstrated a THA-induced increase in the release of endogenous DA and 5-HT from rat brain tissue prisms (Robinson et al 1989) and [3H]NA from rat cortex slices (Drukarch et al 1988). Furthermore, pretreatment with MEC (2.0mg/kg) completely blocked the THA-induced increase in NA and 5-HT turnover, but only partially blocked DA turnover.…”

“…However, whether this compound is effective in stimulating brain NA and/or 5-HT function has not been clarified. On the other hand, 9-amino-1,2,3,4-tetrahydroacridine (THA), an acetylcholine esterase (ACHE) inhibitor, which is used for the treatment of cognitive impairment in Alzheimer's disease, affects monoaminergic function (Adem et al 1989;Robinson et al 1989).…”

Effectiveness of 1,2,3,4-Tetrahydro-9-aminoacridine (THA) as a pretreatment drug for protection of mice from acute diisopropylfluorophosphate (DFP) intoxication

“…Finally, also the possibility that mechanism(s) other than AChE protection may be involved in THA antidotal action, deserves attention. It is well known that THA has a complicated pharmacology and exerts several actions besides interacting with cholinesterases (Rogawski 1987;Albin et al 1988;Davenport et al 1988;Hunter et al 1989;Robinson et al 1989;Peterson 1990;Thesleff et al 1990). …”

“…Interest in this drug arises mainly from reports indicating that is effective in improving the clinical condition of certain patients with Alzheimer's disease (Summers et al 1989). Although there is growing evidence for other than AChE inhibitory actions (Albin et al 1988;Hunter et al 1989;Robinson et al 1989;Peterson 1990;Thesleff et al 1990), the opinion that THA exerts its beneficial effects primarily by temporarily inhibiting central AChE still seems to prevail over other hypotheses at the moment (Nielsen et al 1989). Previous studies have shown that THA and THA derivatives may exert direct protective action on AChE from various sources against inhibition by organophosphorus compounds (Patocka et al 1976;Bajgar et al 1983;Wu and Yang 1989).…”

Interaction of a Muscarinic Cholinergic Agonist on Acetylcholine and Dopamine Receptors in the Monkey Brain Studied with Positron Emission Tomography

“…The observed changes in binding might probably be due to a direct milameline action on muscarinic autoreceptors which generates an altered concentration of acetylcholine and dopamine in the synaptic cleft. Increased dopamine levels have earlier been measured following the reversible choline esterase inhibitor tacrine in vitro [29, 30]and when perfused into striatal tissue of freely moving rats using microdialysis [31]. The increased synaptic concentrations of dopamine found in those studies correlated with the enhanced acetylcholine concentrations as well as to a direct action of tacrine on muscarinic and nicotinic heteroreceptors.…”