The Gi/o protein-coupled histamine H3 receptor is distributed throughout the 
central nervous system including areas like cerebral cortex, hippocampus and 
striatum with the density being highest in the posterior hypothalamus, i.e. the 
area in which the histaminergic cell bodies are located. In contrast to the 
other histamine receptor subtypes (H1, H2 and H4), the H3 receptor is located 
presynaptically and shows a constitutive activity. In detail, H3 receptors are 
involved in the inhibition of histamine release (presynaptic autoreceptor), 
impulse flow along the histaminergic neurones (somadendritic autoreceptor) and 
histamine synthesis. Moreover, they occur as inhibitory presynaptic 
heteroreceptors on serotoninergic, noradrenergic, dopaminergic, glutamatergic, 
GABAergic and perhaps cholinergic neurones. This review shows for four functions 
of the brain that the H3 receptor represents a brake against the wake-promoting, 
anticonvulsant and anorectic effect of histamine (via postsynaptic H1 receptors) 
and its procognitive activity (via postsynaptic H1 and H2 receptors). Indeed, H1 
agonists and H3 inverse agonists elicit essentially the same effects, at least 
in rodents; these effects are opposite in direction to those elicited by 
brain-penetrating H1 receptor antagonists in humans. Although the benefit for H3 
inverse agonists for the symptomatic treatment of dementias is inconclusive, 
several members of this group have shown a marked potential for the treatment of 
disorders associated with excessive daytime sleepiness. In March 2016, the 
European Commission granted a marketing authorisation for pitolisant (WakixR) 
(as the first representative of the H3 inverse agonists) for the treatment of 
narcolepsy.