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20 octobre 2002
 Europ J of Pharmacology 2001;415:157-164
 Central and peripheral activity of cholinesterase inhibitors as revealed by yawning ans fasciculation in rats
H Ogura, T Kasasa, Y Kuriya, Y Yamanishi
Tsukuda Res Labo, Eisai Co, Tsukuba, Ibaraki Japan


Philibert C, Sauveplane K, Pinzani-Harter V et al. Le bâillement: de la physiologie à la iatrogénie. La lettre du pneumologue. 2011;14(5):168-172
Introduction : Cholinesterase inhibitors are, so far, the only successful strategy for the symptornatic treatment of Alzheimer's disease. Cholinesterase is the enzyme that is responsible for the hydrolysis of acetylcholine. Cholinesterase inhibitors both block this metabolisin of acetylcholine, thus increasing the level of acetylcholine in the synaptic cleft, and activate cholinergic transmission. An important prerequisite for the use of cholinesterase inhibitors in Alzheimer's disease therapy is a preferential action in the central, versus peripheral, nervous system.
Activation of central cholinergic system, elicits yawning in experimental animals. Urba-Holmgren described that pilocarpine, a muscarinic receptor agonist and physostigmine, a cholinesterase inhibitor, induced yawning in rats, while neostigimine, which passes the blood-brain barrier with difficulty, did not induce yawning. Scopolamine, a centrally acting muscarinic receptor antagonist, inhibited yawning induced by cholinergic activation, but the peripheral muscarinic antagonist, methylscopolamine, did not. These findings suggest that the yawning is induced by central cholinergic activation.
Thus, the elicitation of yawning by cholinesterase inhibitors can be used as a useful index for their action within the central nervous system.
Cholinesterase inhibitors cause a variety of peripheral cholinergic effects. Fasciculation is characterized by a fine involuntary movement of muscles and is a consistent measurement among peripheral cholinergic signs . Facilitation of cholinergic transmission at the neuromuscular junction by cholinesterase inhibitors leads to fasciculation. We now demonstrated the hight relationship between induction of fasciculation by intravenous administration of cholinesterase inhibitors and in vitro inhibitory activity on acetylcholinesterase. It was suggested that fasciculation is a reliable index of peripheral cholinergic activation by cholinesterase inhibitors. In addition, we compared the potencies of several cholinesterase inhibitors to activate central and peripheral cholinergic system by concurrent monitoring of yawning and fasciculation. This experimental design allows for a clear assessment of the central and peripheral profiles of cholinesterase inhibitors. Furthermore, the involvement of cholinergic and dopaminergic mechanisms in yawning induced by E2030, (3-(2-(1-(1,3dioxolan-2-ylmethyl)-4-piperidyl)ethyl)-2 H-3,4-dihydro1,3-benzoxazin-2,4-dione hydrochloride), a novel centrally acting cholinesterase inhibitor, was investigated. [...]
Discussion : In this study, the proportion of central versus peripheral cholinergic activity of a number of cholinesterase inhibitors was clarified. E2030 and donepezil were found to potently and preferentially activate the central cholinergic system, as indicated by a marked induction of yawning in rats, while having relatively little effect on the intensity of fasciculation, a peripheral cholinergic marker.
Fasciculation is observed when cholinergic transmission at the neuromuscular junction is prompted. The subtype of acetylcholine receptors in muscles is nicotinic, and it is thus not surprising that scopolamine did not inhibit the fasciculation induced by donepezil or E2030, as shown here, or by physostigmine and distigmine (data not shown). In this study, fasciculation produced by intravenous cholinesterase inhibitors was tightly correlated with the in vitro activity of acetylcholinesterase inhibition, but not of butyrylcholinesterase inhibition. This suggests that the occurrence of fasciculation depends on the in vitro activity of cholinesterase inhibitors, as well as their plasma concentrations, and quite independently of the brain permeability of each compound. This evidence supports the use of fasciculation as a good marker of peripheral cholinergic activation. Furthermore, it suggests that acetylcholinesterase, but not butyrylcholinesterase, is involved in cholinergic transmission at the neuromuscular junction.
Results of this study further support the idea that yawning elicited by cholinesterase inhibitors is a result of central cholinercic activation. For example, among several cholinesterase inhibitors tested, distigmine, which is a peripherally acting cholinesterase inhibitor, did not elicit yawning. This observation was consistent with results of an early study showing that the peripherally acting cholinesterase inhibitor, neostigmine, did not cause yawning. Moreover, the centrally acting muscarinic receptor antaaonist, scopolamine, completely blocked E2030-induced yawning, while the peripherally acting muscarinic receptor antagonist, methylscopolamine, had no effect on yawning.
Similar results were obtained in the case of other cholinesterase inhibitors as well as muscarinic agonists. It is not clear which brain sites are involved in yawning induced by cholinergie activation. Oxytocin was found to induce yawning when injected into the hippocampus showed that yawning could be induced by neuropeptides like a-MSH (et-melanocyte stimulating hormone) or ACTH (adrenocorticotropic hormone), and this was associated with an increase in hippocampal acetylcholine turnover rate. Some cholinesterase inhibitors used in the prescrit study have also been shown to enhance the basal concentration of extracellular acetylcholine in the hippocampus of rats. Therefore, it is possible that the hippocampus is an important site involved in yawning induced by cholinomimetics.
Putative centrally acting cholinesterase inhibitors were found to elicit yawning, suggesting that the study design we used here meets the criterion of face validity to assess central cholinergie activity. When comparing the effective doses to elicit yawning and fasciculation, E2030 was the only compound that elicited yawning at a dose (4 mg/kg), which was less than the dose (16 mg/kg) necessary to induce fasciculation. Donepezil, tacrine, and physostigmine elicited both yawning and fasciculation at the same doses. Ipidacrine elicited fasciculation more effectively than yawning (i.e., half the dose). We found, however, that TAK-147, which is currently in clinical trials for Alzheimer's disease in Japan, was not very effective to cause yawning. We previously reported on the effects of donepezil, tacrine and TAK-147 on extracellular acetylcholine concentrations in the cerebral cortex of rats. The rank order comparing the values of the ratio of the minimum effective dose for acetylcholine-increasing action to that for the fasciculation-producing action was: donepezil > tacrine > TAK-147. These results correspond well with the resulis of the prescrit study.
Analysis of central and peripheral balance classified cholinesterase inhibitors approxiinately into three categories. Donepezil and E2030 are in the first group, and show a strong preference toward central cholinergie system activation. Compounds like tacrine, ipidacrine, and physostiginine are in the second category and have an equipotent degree of central and peripheral action. Distigmine can be classified in a third category of peripherally acting cholinesterase inhibitors. In this context, TAK-147 may be in the middle of the second and third categories. The central and peripheral balance for each compound depends mainly on brain permeability and partly on selectivity for acetylcholinesterase. We previously showed that donepezil was more potent than tacrine to improve leaming impairments in some hypocholinergic models using rats. This finding, in general, is consistent with the prescrit results.
It is well known that dopaminergic systems also are involved in the induction of yawning. Scopolamine blocks yawning induced by both cholinomimetics and dopamine receptor agonists such as apomorphine, while haloperidol, a dopamine receptor antagonist, inhibits yawning induced by dopamine receptor agonists, but not cholinomimetics such as physostigmine, tacrine, ipidacrine, and pilocarpine. In this study, we confirmed that E2030-induced yawning was blocked by scopolamine. Interestingly, haloperidol, which did not affect donepezil-induced yawning, partially inhibited E2030-induced yawning. It is not apparent why haloperidol inhibited yawning only after the highest dose of E2030, but only high doses of E2030 may produce additional dopamie mediated effects on yawning, which can be blocked by haloperidol. These results suggest that the doparninergic system might be partially involved in E2030-induced yawning, and that the underlying mechanisin is different from that of donepezil.
This study sheds light on the central and peripheral balance of action of cholinesterase inhibitors. Among cholinesterase inhibitors tested, donepezil and E2030 have a superior ability to enhance central cholinergic transmission preferentially. E2030 may have a suitable balance of central cholinergic action for symptomatic therapy in the treatment of Alzheimer's disease as well as donepezil, which is prescribed worldwide.
Stretchings and yawnings induced by adrenocorticotrophic hormone GL Gessa
Drugs affecting dopamine neurons ans yawning behavior Mogilnicka E, Klimek V
Paraventricular nucleus lesion prevents yawning and penile erection induced by apomorphine and oxytocin but not by ACTH in rats Argiolas A
Hypophysectomy prevents yawning and penile erection but not hypomotility induced by apomorphine Serra G
ACTH and alpha-MSH induced grooming, stretching, yawning and penile erection in male rats: site of action in the brain and role of melanocortin receptors Argiolas A
Yawning and penile erection: central dopamine-oxytocin-adrenocorticotropin connection Argiolas A
Reduction of drug-induced yawning and penile erection by the activation of GABAa receptors in the paraventricular nucleus: involvement of nitric oxide MR Melis, A Argiolas
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