| 1 The effects of histamine on MK-801-induced spatial memorydeficits in SD ratsHistamine is a neurotransmitter which plays an important role in learning and memory. Recently, the interactions between histamine and NMDA receptor have attracted considerable attentions. It was discovered in cultured hippocampal pyramidal cells that histamine could dramatically enhance NMDA receptor-mediated synaptic transmission. However, few behavioral studies were made on the interaction of histamine and NMDA receptors in cognition process. We have previously reported histamine reversed memory deficits of rats induced by MK-801 in 8-arm radial maze performance. However, little is known about the involvement of the hippocampal NMDA receptor in amelioration of histaminergic system and it remains to be unknown whether working memory, a kind of short-term memory, or reference memory, a kind of long-term memory, is prominently related to histamine. So our AIM: To investigate whether or not exogenous and endogenous histamine is involved in spatial memory deficits induced by dizocilpine (MK-801) as evaluated by 8-arm radial maze of rats. METHODS: 8-Arm (4-arm baited) radial maze was used to measure spatial memory in rats. RESULTS: Bilaterally intrahippocampal (ih) injection of MK-801 (0.3 g/site) impaired working memory and reference memory in rats. Both histamine (50, 100 ng/site, ih) and intraperitoneal (ip) injection of histidine (100, 200 mg/kg) markedly improved the spatial memory deficits induced by MK-801. The ameliorating effect of histidine (100 mg/kg, ip) was completely antagonized by -fluoromethylhistidine ( -FMH, 5 ug/site, ih), a potent and selective histidine decarboxylase (HDC) inhibitor. In addition, H]-antagonist pyrilamine (1 ug/site, ih), but not by H2-antagonist cimetidine, reversed the ameliorating effect of histidine. Bilaterally intrahippocampal (ih) injection of clobenpropit (5, 10 g/site) markedly improved working and reference memory deficits induced by MK-801, and its ameliorating effect was potentiated by histidine, and completely antagonized by immepip (2.5 g/site), a selective H3-agonist. -FMH (10, 25 g/site) antagonized the ameliorated effect of clobenpropit on the working memory deficits induced by MK-801. In addition, H1-antagonist pyrilamine (1 g/site,ih), but not by H2-antagonist cimetidine, reversed the working memory ameliorating effect of clobenpropit. Both a-FMH and pyrilamine did not significantly modulate the effect of clobenpropit on reference memory. CONCLUSIONS: The results indicate that both exogenous histamine and endogenous histamine plays an important role in the ameliorating effect on MK-801 -induced spatial memory deficits, and its action is mediated through postsynaptic HI-receptor. H3 receptor antagonists also ameliorate MK-801-induced spatial memory deficits, and its action on working and reference memory might be due to different mechanisms. The amelioration of working memory deficit is mediated by increasing hippocampal endogenous histamine release and activation of postsynaptic H1-receptor whereas the effects on reference memory might be due to the increased release of neurotransmitters other than histamine. Our data further corroborate the suggested potential therapeutic application of H3-antagonists in conditions with memory deficits, like Alzheimer's disease.2 The effect of histamine on NMDA-induced neuron deathOur recent research reveal the interaction between histamine and NMDA receptor. NMDA-induced neuron death is known to be the pathology change of memory deficits, so the amelioration of histamine on memory deficits might be due to reduce the neuron death. But to date there is no research about it in cell culture.On the other hand, the research about the relationship between histamine and NMDA reach controversial results, which may be due to the different dose of histamine. So our AIM: To determine the effect of histamine on NMDA-induced neuron death and to elucidate the mechanism. Methods: The pr... |
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