Melchers B P, van der Laaken A L, Busker R W, Bruijnzeel P L, Van Helden H P
Department of Pharmacology, TNO-Pharma, Rijswijk, The Netherlands.
Arch Toxicol. 1994;69(2):118-26. doi: 10.1007/s002040050146.
Effects of the oxime HI-6, unrelated to reactivation of acetylcholinesterase (AChE), on field potentials in the dentate gyrus of the rat hippocampus following AChE inhibition, were investigated both in vitro and in vivo. In hippocampal slices, AChE inhibition decreased the perforant path evoked population spike amplitude (PSA). This effect could be prevented by pre-incubation of the slices with atropine (0.1-1 microM) or with the M1 muscarinic receptor antagonist pirenzepine (1 microM). A similar preventive effect was found after pre-incubation with the GABAA antagonist picrotoxin (20 microM), suggesting that the effects of AChE inhibition in vitro may be due to an enhancement of GABAergic inhibitory activity via activation of M1-muscarinic receptors. The effects of AChE inhibition in vivo were variable; both increases and decreases of the PSA were found. Following AChE inhibition, HI-6 increased the PSA dose-dependently, both in the in vivo and in the in vitro hippocampus. At higher oxime doses the perforant path stimulation elicited multiple population spikes. The effects of the oxime were presumably not mediated by an antagonism of cholinergic receptors, since they could not be mimicked with cholinergic antagonists like atropine, mecamylamine or gallamine. Further testing of the nature of the HI-6 effect in hippocampal slices in vitro, using a paired antidromic-orthodromic stimulation protocol, showed that HI-6 may interfere with GABAergic inhibition.
研究了与乙酰胆碱酯酶（AChE）复能无关的肟HI-6对大鼠海马齿状回在AChE抑制后场电位的体内和体外影响。在海马切片中，AChE抑制降低了穿通通路诱发的群体峰电位幅度（PSA）。用阿托品（0.1 - 1微摩尔）或M1毒蕈碱受体拮抗剂哌仑西平（1微摩尔）预孵育切片可预防这种效应。用GABAA拮抗剂荷包牡丹碱（20微摩尔）预孵育后也发现了类似的预防作用，这表明体外AChE抑制的效应可能是由于通过激活M1毒蕈碱受体增强了GABA能抑制活性。AChE抑制在体内的效应是可变的；PSA既有增加也有减少。AChE抑制后，HI-6在体内和体外海马中均剂量依赖性地增加PSA。在较高的肟剂量下，穿通通路刺激引发多个群体峰电位。肟的效应可能不是由胆碱能受体拮抗介导的，因为它们不能被阿托品、美加明或加拉明等胆碱能拮抗剂模拟。使用配对的逆向-正向刺激方案在体外海马切片中进一步测试HI-6效应的性质，结果表明HI-6可能干扰GABA能抑制。
