Department of Anesthesiology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanasawa-Ku, Yokohama 236-0004, Japan
*Corresponding author. E-mail: inagawa@med.yokohama-cu.ac.jp
Accepted for publication: September 24, 2003
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Abstract |
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Methods. We studied the effects of the depressant and convulsant MPPB stereoisomers on rat hippocampal acetylcholine (ACh) release in vivo, using a brain microdialysis technique in freely moving animals.
Results. R()-MPPB 60 and 90 mg kg1 i.p. decreased ACh release from the rat hippocampus by 44.1 (8.2)% and 60.8 (8.2)%, respectively. In the hippocampus, the local application of bicuculline, a -aminobutyric acid (GABA)A receptor antagonist, 1 µmol litre1 antagonized the inhibitory effects of R()-MPPB 90 mg kg1 i.p. In contrast, R()-MPPB, S(+)-MPPB 60 and 90 mg kg1 i.p. increased ACh release to 151.8 (6.8)% and 169.6 (11.1)% of the basal release, respectively.
Conclusions. Our results demonstrated that R()-MPPB decreased, while S(+)-MPPB increased, rat hippocampal ACh release and that the inhibitory effects of R()-MPPB may involve the GABAA receptor in vivo. These data imply that changes in hippocampal ACh due to these agents may be related to their central inhibitory and stimulatory actions in vivo.
Br J Anaesth 2004; 92: 4246
Keywords: brain, acetylcholine; brain, microdialysis; isomer, R()-MPPB; isomer, S(+)-MPPB
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Introduction |
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Methods and results |
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All results are expressed as mean (SEM) and values are expressed as a percentage of basal ACh release. The basal release was obtained from the average of the three initial collections before administration of the test drugs. The significance of the differences among the corresponding samples obtained in different conditions was analysed by one-way ANOVA followed by Fishers protected least significant difference test for multiple comparisons. P<0.05 was accepted as significant.
Baseline ACh release (with no correction for recovery) from the rat hippocampus in a 20 min sample was 2.2 (0.1) pmol/20 min (n=20). As shown in Fig. 1A, R()-MPPB 60 and 90 mg kg1 i.p. significantly decreased basal ACh release from the rat hippocampus by 44.1 (8.2) and 60.8 (8.2)%, respectively. Contrary to R()-MPPB, S(+)-MPPB 60 and 90 mg kg1 i.p. increased ACh release to 151.8 (6.8) and 169.6 (11.1)% of the basal release, respectively (Fig. 1B). Local hippocampal application of bicuculline 1 µmol litre1 significantly antagonized the inhibitory effect of R()-MPPB 90 mg kg1 i.p., while local perfusion of bicuculline 1 µmol litre1 alone did not alter basal release from the hippocampus (Fig. 1C). In a separate group of animals (n=20, 5 for each condition), we confirmed that R()-MPPB 60 and 90 mg kg1 caused LRR and that S(+)-MPPB at the same doses induced convulsions.
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Comment |
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Central cholinergic neurons are distributed widely in the CNS and may be involved in unconsciousness induced in general anaesthesia. In rats, a decrease in the central ACh levels has been shown to increase anaesthetic potency of isoflurane and elevating ACh was shown to increase the anaesthetic requirement.4 Another study demonstrated that physostigmine, a cholinesterase-inhibitor, reversed propofol-induced unconsciousness in human volunteers. The reversal of unconsciousness was blocked by pretreatment with scopolamine.5 These findings suggest that central cholinergic transmission may play an important role during anaesthesia. The hippocampus receives abundant cholinergic extrinsic innervations from the medial septal area containing choline acetyltransferase-positive neurons.6 7 A recent study showed that inactivation of the medial septum or hippocampus by local injection of a GABAA receptor agonist exaggerated the behavioural response to general anaesthetics, including the volatiles, pentobarbital and propofol, suggesting that the septohippocampal system participates in general anaesthesia.8 Because inactivation of the septohippocampal system probably leads to a decrease in hippocampal ACh release, it is likely that the modulation of hippocampal ACh release plays a role in anaesthetic action.
MPPB isomers are known to exhibit contrasting actions on GABAA receptors, with stimulation by the depressant and inhibition by the convulsant.9 10 It is likely that the correlation between hippocampal ACh levels and behaviour mainly stems from the opposite effects on the GABAA receptor function caused by the stereoisomers, as modulation of the GABAA receptor function probably contributes to the changes in ACh release, as well as the behavioural effects induced by these agents. However, increased or decreased ACh levels in the hippocampus could causally induce alteration of some neuronal function by depressant and convulsant barbiturates, such as cognitive dysfunction and changes in consciousness, although this is pure speculation.
In summary, depressant R()-MPPB decreased, while convulsant S(+)-MPPB increased, hippocampal ACh release in vivo in the rat, implying that changes in hippocampal ACh release may be related to the behavioural effects of barbiturates. The significance of these findings remains to be elucidated.
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References |
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