Fasting activated histaminergic neurons and enhanced arousal effect of caffeine in mice

• Caffeine enhanced locomotor activity in fasted mice for 5 h, but only for 3 h in normally fed animals.
• H1R antagonist pyrilamine abolished the effect of caffeine on locomotor activity in fasted mice.
• Caffeine induced wakefulness for 3 h in fed WT mice, and for 5 h in fasted ones.
• A stimulatory effect of caffeine was not observed in fasted H1R KO mice.
• Caffeine had greater wakefulness-promoting effects in fasted mice via H1R.

Caffeine, a popular psychoactive compound, promotes wakefulness via blocking adenosine A2A receptors in the shell of the nucleus accumbens, which projects to the arousal histaminergic tuberomammillary nucleus (TMN). The TMN controls several behaviors such as wakefulness and feeding. Fasting has been reported to activate the TMN histaminergic neurons to increase arousal. Therefore, we propose that caffeine may promote greater arousal under fasting rather than normal feeding conditions. In the current study, locomotor activity recording, electroencephalogram (EEG) and electromyogram recording and c-Fos expression were used in wild type (WT) and histamine H1 receptor (H1R) knockout (KO) mice to investigate the arousal effects of caffeine under fasting conditions. Caffeine (15 mg/kg) enhanced locomotor activity in fasted mice for 5 h, but only did so for 3 h in normally fed animals. Pretreatment with the H1R antagonist pyrilamine abolished caffeine-induced stimulation on locomotor activity in fasted mice. EEG recordings confirmed that caffeine-induced wakefulness for 3 h in fed WT mice, and for 5 h in fasted ones. A stimulatory effect of caffeine was not observed in fasted H1R KO mice. Furthermore, c-Fos expression was increased in the TMN under fasting conditions. These results indicate that caffeine had greater wakefulness-promoting effects in fasted mice through the mediation of H1R.