The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders.

Histamine H3 receptor pharmacology, functions and biochemistry are far from being fully understood; however, progress is being made. Activation of this Gi/GO-protein-coupled receptor affects cognition, the sleep-wake cycle, obesity and epilepsy, which are physiological and pathological conditions that are the main focus of research into the therapeutic potential of selective H3 receptor ligands. This heterogeneity of targets can be reconciled partially by the fact that the histamine system constitutes one of the most important brain-activating systems and that H3 receptors regulate the activity of histamine and other neurotransmitter systems. Furthermore, the H3 receptor shows functional constitutive activity, polymorphisms in humans and rodents with a differential distribution of splice variants in the CNS, and potential coupling to different intracellular signal transduction mechanisms. In light of the genetic, pharmacological and functional complexity of the H3 receptor, the importance of the histamine system as a therapeutic target to control the sleep-wake cycle and cognitive disorders will be discussed.