Effects of l-histidine and histamine H3 receptor modulators on ethanol-induced sedation in mice

Recent studies suggest that the brain histaminergic system and especially the H3 receptors are involved in the regulation of alcohol consumption and alcohol-induced behaviors. Part of this effect might be due to a modulation of ethanol-induced sedation by central histamine. The aim of the present study was to investigate the effects of several histaminergic drugs on ethanol-induced sedation using the loss of righting reflex experimental protocol in female Swiss mice. A pretreatment with L-histidine, the histamine precursor, significantly reduced ethanol-induced sedation, suggesting that brain histamine protects against the sedative effects of ethanol. In a second set of experiments, several H3 receptor agonists (immepip or imetit) and inverse agonists/antagonists (thioperamide, A331440, or BF2.649) were tested. Surprisingly, both H3 receptor agonists and antagonists potentiated the sedative effects of ethanol. This paradoxical effect might be due to the subtle regulatory actions related to the H3 heteroreceptor function.