The histamine H 3 receptor: an attractive target for the treatment of cognitive disorders

The histamine H 3 receptor, first described in 1983 as a histamine autoreceptor and later shown to also function as a heteroreceptor that regulates the release of other neurotransmitters, has been the focus of research by numerous laboratories as it represents an attractive drug target for a number of indications including cognition. The purpose of this review is to acquaint the reader with the current understanding of H 3 receptor localization and function as a modulator of neurotransmitter release and its effects on cognitive processes, as well as to provide an update on selected H 3 antagonists in various states of preclinical and clinical advancement. Blockade of centrally localized H 3 receptors by selective H 3 receptor antagonists has been shown to enhance the release of neurotransmitters such as histamine, ACh, dopamine and norepinephrine, among others, which play important roles in cognitive processes. The cognitive‐enhancing effects of H 3 antagonists across multiple cognitive domains in a wide number of preclinical cognition models also bolster confidence in this therapeutic approach for the treatment of attention deficit hyperactivity disorder, Alzheimer's disease and schizophrenia. However, although a number of clinical studies examining the efficacy of H 3 receptor antagonists for a variety of cognitive disorders are currently underway, no clinical proof of concept for an H 3 receptor antagonist has been reported to date. The discovery of effective H 3 antagonists as therapeutic agents for the novel treatment of cognitive disorders will only be accomplished through continued research efforts that further our insights into the functions of the H 3 receptor. British Journal of Pharmacology (2008) 154 , 1166–1181; doi: 10.1038/bjp.2008.147 ; published online 12 May 2008