Selbach O, Brown R E, Haas H L
Department of Physiology II, Heinrich-Heine-University, Düsseldorf, Germany.
Neuropharmacology. 1997 Nov-Dec;36(11-12):1539-48. doi: 10.1016/s0028-3908(97)00144-5.
The action of histamine (HA) on rat hippocampal CA1 pyramidal cells in vitro was investigated in slices perfused with solution containing 0.2 mM Ca2+/4.0 mM Mg2+. Extracellular recordings of the spontaneous discharges occurring under these conditions revealed that HA caused a long-lasting increase in cell firing. The HA-effects were dose-dependent, in that low concentrations of HA (0.1-0.5 microM) exhibited an initial transient depression of cell firing and practically no long-lasting action, whereas higher concentrations of HA (1-10 microM) exerted strong, non-declining increases. The H1-receptor antagonist mepyramine (1 microM) blocked the initial depression of firing and attenuated the long-lasting HA-mediated excitation. Pure H1-receptor activation, tested with the H1-receptor agonist 2-(3-fluorphenyl)histamine (1-10 microM) depressed cell firing, similar to the low dose effects of HA. HA-induced excitations were prevented by the H2-receptor antagonist cimetidine (10-50 microM), and mimicked by the very potent H2-receptor agonist impromidine (1 or 3 microM) which was, however, less effective compared to equal concentrations of HA. H3-receptor activation by R-alpha-methylhistamine had no significant effect on cell firing. Thus, histamine H1 and H2 receptors seem to cooperate in producing this long-lasting augmentation of excitability. 8-Bromo-cyclic AMP monophosphate (8-Br-cAMP, 50-100 microM) mimicked the long-term excitation, whereas the adenylyl-cyclase inhibitor 9-tetrahydro-2-furyladenine (THFA, 100-500 microM) or the PKA-inhibitor Rp-adenosine-3'5'-cyclic monophosphate (Rp-cAMPS, 10 microM) blocked it, indicating that the HA-mediated increase of excitability in the hippocampus is dependent on the adenylate cyclase/PKA-signal transduction cascade. DL-2-Amino-5-phosphonopentanoic acid (APV, 50 microM) significantly attenuated the magnitude of the HA-induced enhancement, indicating an NMDA receptor-dependent component. Other biogenic amines, acting through receptors positively coupled to adenylyl cyclase, elicited similar responses as HA, indicating common mechanisms by which these substances modulate excitability in CA1 pyramidal cells.
在灌注含0.2 mM Ca2+/4.0 mM Mg2+溶液的脑片中，研究了组胺（HA）对大鼠海马CA1锥体神经元的作用。细胞外记录这些条件下的自发放电显示，HA引起细胞放电的持续增加。HA的作用呈剂量依赖性，低浓度HA（0.1 - 0.5 microM）最初短暂抑制细胞放电且几乎无持久作用，而高浓度HA（1 - 10 microM）则产生强烈、不衰减的增加。H1受体拮抗剂美吡拉敏（1 microM）阻断了最初的放电抑制并减弱了HA介导的持久兴奋。用H1受体激动剂2 - (3 - 氟苯基)组胺（1 - 10 microM）测试纯H1受体激活时，细胞放电受到抑制，类似于低剂量HA的作用。HA诱导的兴奋被H2受体拮抗剂西咪替丁（10 - 50 microM）阻断，且被强效H2受体激动剂英普咪定（1或3 microM）模拟，然而，与相同浓度的HA相比，其效果较差。R - α - 甲基组胺激活H3受体对细胞放电无显著影响。因此，组胺H1和H2受体似乎协同作用产生这种兴奋性的持久增强。8 - 溴环磷酸腺苷（8 - Br - cAMP，50 - 100 microM）模拟了长期兴奋，而腺苷酸环化酶抑制剂9 - 四氢 - 2 - 呋喃基腺嘌呤（THFA，100 - 500 microM）或PKA抑制剂Rp - 腺苷 - 3',5' - 环磷酸（Rp - cAMPS，10 microM）阻断了它，表明HA介导的海马兴奋性增加依赖于腺苷酸环化酶/PKA信号转导级联。DL - 2 - 氨基 - 5 - 膦酰戊酸（APV，50 microM）显著减弱了HA诱导增强的幅度，表明存在NMDA受体依赖性成分。其他通过与腺苷酸环化酶正偶联的受体起作用的生物胺，引发了与HA相似的反应，表明这些物质调节CA1锥体神经元兴奋性的共同机制。
