1 The effect of tetrahydroaminoacridine (THA) on cholinergically mediated behaviour in the rat and mouse has been investigated. In addition the actions of this compound on cholinesterase activity and on muscarinic and nicotinic receptors has also been examined. 2 Administration of THA (5-20mgkg-1, i.p.) produced a dose-dependent increase in tremor, hypothermia and salivation in both rats and mice. A similar profile of activity was seen following physostigmine (0.1-0.6 mg kg -1) administration. 3 THA was approximately fifty fold less potent than physostigmine in inducing behavioural change but its effects persisted for over twice as long as those of physostigmine. For example THA-induced hypothermia was still present at 4 h in the mouse and 8 h in the rat. 4 In vitro THA was a potent non-competitive inhibitor of rat brain cholinesterase (IC50: 57 + 6 nM) and bovine erythrocyte acetylcholinesterase (IC50: 50 + 10 nm) but was a more potent inhibitor of horse serum butyrylcholinesterase (IC50: 7.2 + 1.4 nM). 5 Radioligand binding studies indicated that THA binds non-selectively but with moderate potency to both M1 (Ki: 600nM) and M2 (Ki: 880nM) muscarinic receptors. THA also interacted with the allosteric site present on cardiac M2 receptors.
Male rats were tested in a simple olfactory habituation and discrimination paradigm. Untreated rats habituated their responses over three trials to one odour but were capable of recognising a novel odour presented on the fourth trial. Administration (SC) of either scopolamine or N-methylscopolamine before trials commenced produced a decrease in overall responding. Scopolamine, but not N-methylscopolamine, also blocked habituation to the first odour and recognition to the second, novel odour. Administration of scopolamine after trial 3 did not block the ability of the animals to respond differentially to a novel odour, although again overall levels of responding were decreased. Electrolytic lesions of the medial septal area increased overall levels of responding but lesioned animals still habituated their response over trials and were capable of recognising a novel odour. Therefore although cholinergic mechanisms appear to be involved in this type of learning, these effects are unlikely to be mediated via the septohippocampal system.
1 Xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine] has been reported to act as a functionally selective muscarinic partial agonist with potential use in the treatment of Alzheimer's disease. This study examined the functional activity of xanomeline at 5-HT 1 and 5-HT 2 receptors in native tissue and/or human cloned receptors. 3, was not attenuated by pirenzepine up to 3 mM and was inhibited by the selective 5-HT 1A antagonist WAY100635 with an apparent pK b of 9.4. These data suggest the agonist e ect of xanomeline in this tissue is, in part, via 5-HT 1A receptors. Similar studies on human cloned receptors con®rmed that xanomeline is an agonist at human cloned 5-HT 1A and 5-HT 1B receptors. 4 In studies using the¯uorescent cytoplasmic Ca 2+ indicator FLUO-3AM, xanomeline induced an increase in cytoplasmic Ca 2+ concentration in SH-SY5Y cells expressing recombinant human 5-HT 2C receptors. Atropine antagonized this response, consistent with mediation via endogenously-expressed muscarinic receptors. In the presence of atropine, xanomeline antagonized 5-HT-induced cytoplasmic changes in Ca 2+ concentration in cells expressing h5-HT 2A , h5-HT 2B and h5-HT 2C receptors with potencies similar to its a nity at these receptors. 5 These studies indicate that xanomeline is a potent agonist at 5-HT 1A and 5-HT 1B receptors and an antagonist at 5-HT 2 receptor subtypes.
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