Roles of histamine in regulation of arousal and cognition: Functional neuroimaging of histamine H1 receptors in human brain

Brain histamine is involved in a wide range of physiological functions such as regulation of the sleep-wake cycle, arousal, cognition, and memory mainly through interactions with histamine H1 receptors (H1Rs). Neurons producing histamine, histaminergic neurons, are exclusively located in the posterior hypothalamus and transmit histamine to almost all regions of the brain. Histamine H1 antagonists, or antihistamines, often prescribed for treatment of allergic disorders, sometimes induce sleepiness and cognitive deficits. It is understood that the mechanism of such CNS side effects is that antihistamine blocks H1Rs in the brain. The purpose of the present study was to compare the CNS side effects of different antihistamines. Subjective sleepiness was measured using the Stanford Sleepiness Scale (SSS) and psychomotor performance was examined by a tachistoscope testing system in healthy, young, Japanese volunteers (16 males, 20-28 yrs.) before and after oral administration of antihistamines such as fexofenadine (FEX) and cetirizine (CET). Additionally, H1R occupancy by antihistamines was examined by PET with ¹¹C-doxepin in 8 volunteers. The results of SSS and psychomotor tests demonstrated that FEX tended to be less sedative than CET though the difference was not statistically significant. PET measurements revealed that no H1Rs in the cerebral cortex were occupied by FEX while about 30% of H1Rs were occupied by CET. In summary, it was confirmed that histamine and H1Rs are involved in maintaining arousal and cognition in humans, and that the severity of clinical symptoms is correlated to the amount of antihistamine that penetrated into the brain.