Prast H, Tran M H, Fischer H, Kraus M, Lamberti C, Grass K, Philippu A
Institut für Pharmakologie und Toxikologie der Universität Innsbruck, Austria.
Naunyn Schmiedebergs Arch Pharmacol. 1999 Nov;360(5):558-64. doi: 10.1007/s002109900097.
To investigate whether histaminergic neurons influence the activity of cholinergic neurons, the ventral striatum was superfused through a push-pull cannula and the release of endogenous acetylcholine was determined in the superfusate. Local inhibition of histamine synthesis by superfusion with alpha-fluoromethylhistidine (FMH) gradually decreased the release rate of acetylcholine. Superfusion with histamine increased the release of acetylcholine. The releasing effect of histamine was greatly inhibited when the striatum was simultaneously superfused with the D2/D3 agonist quinpirole and the D1 antagonist (+/-)-7-bromo-1-(fluoresceinylthioureido)phenyl-8-hydroxy-3-methyl -2,3,4,5-tetrahydro-1H-3-benzapine (SKF 83566). The effect of histamine on acetylcholine release was abolished by the GABA(A) receptor antagonist bicuculline. Superfusion with the H3 receptor agonists imetit or immepip increased acetylcholine release rate in the striatum. The releasing effects of the two H3 agonists were FMH resistant, while superfusion with quinpirole and SKF 83566 abolished the H3 receptor agonist-induced acetylcholine release. Superfusion with the H3 receptor antagonist thioperamide enhanced acetylcholine release rate. The releasing effect of thioperamide was abolished after inhibition of histamine synthesis by FMH. The release of acetylcholine by thioperamide was also abolished on simultaneous superfusion with quinpirole and SKF 83566. The findings show that, in the striatum, the activity of cholinergic neurons is permanently modulated by neighbouring histaminergic nerve terminals and axons. The release of acetylcholine is also permanently inhibited by neighbouring GABAergic neurons. The enhanced release of acetylcholine by the H3 receptor agonists imetit and immepip is due to stimulation of H3 heteroreceptors, while the increase of acetylcholine release by the H3 receptor antagonist thioperamide is elicited via blockade of H3 autoreceptors. Histamine released from histaminergic nerve terminals increases the release of acetylcholine in part by inhibition of dopamine release which, in turn, decreases GABAergic transmission. A dopamine-independent way seems also to be involved in the histamine-evoked acetylcholine release.
为研究组胺能神经元是否影响胆碱能神经元的活性，通过推挽式套管对腹侧纹状体进行灌流，并测定灌流液中内源性乙酰胆碱的释放量。用α-氟甲基组胺（FMH）灌流局部抑制组胺合成，可使乙酰胆碱的释放速率逐渐降低。用组胺灌流可增加乙酰胆碱的释放。当纹状体同时用D2/D3激动剂喹吡罗和D1拮抗剂（±）-7-溴-1-（荧光素硫脲基）苯基-8-羟基-3-甲基-2,3,4,5-四氢-1H-3-苯并氮杂卓（SKF 83566）灌流时，组胺的释放作用受到极大抑制。GABA（A）受体拮抗剂荷包牡丹碱可消除组胺对乙酰胆碱释放的作用。用H3受体激动剂碘美替或咪哌灌流可增加纹状体中乙酰胆碱的释放速率。两种H3激动剂的释放作用对FMH具有抗性，而用喹吡罗和SKF 83566灌流可消除H3受体激动剂诱导的乙酰胆碱释放。用H3受体拮抗剂硫代哌啶灌流可提高乙酰胆碱的释放速率。FMH抑制组胺合成后，硫代哌啶的释放作用消失。同时用喹吡罗和SKF 83566灌流时，硫代哌啶对乙酰胆碱的释放作用也消失。研究结果表明，在纹状体中，胆碱能神经元的活性受到相邻组胺能神经末梢和轴突的持续调节。相邻的GABA能神经元也可持续抑制乙酰胆碱的释放。H3受体激动剂碘美替和咪哌增强乙酰胆碱释放是由于刺激了H3异受体，而H3受体拮抗剂硫代哌啶增加乙酰胆碱释放是通过阻断H3自身受体引起的。组胺能神经末梢释放的组胺部分通过抑制多巴胺释放来增加乙酰胆碱的释放，而多巴胺释放的减少又会降低GABA能传递。组胺诱发的乙酰胆碱释放似乎还涉及一条不依赖多巴胺的途径。
