Histamine in the brain: Beyond sleep and memory

A few decades elapsed between the attribution of unwanted side effects of classic antihistamine compounds to the blockade of central H1 receptors, and the acceptance of the concept that the histaminergic system commands general states of metabolism and consciousness. In the early 80s, two laboratories discovered independently that histaminergic neurons are located in the posterior hypothalamus and project to the whole CNS [Panula P, Yang HY, Costa E. Histamine-containing neurons in the rat hypothalamus. Proc Natl Acad Sci 1984;81:2572–76, Watanabe T, Taguchi Y, Hayashi H, Tanaka J, Shiosaka S, Tohyama M, Kubota H, Terano Y, Wada H. Evidence for the presence of a histaminergic neuron system in the rat brain: an immunohistochemical analysis. Neurosci Lett 1983;39:249–54], suggesting a global nature of histamine regulatory effects. Recently, functional studies demonstrated that activation of the central histaminergic system alters CNS functions in both behavioral and homeostatic contexts, which include sleep and wakefulness, learning and memory, anxiety, locomotion, feeding and drinking, and neuroendocrine regulation. These actions are achieved through interactions with other neurotransmitter systems, and the interplay between histaminergic neurons and other neurotransmitter systems are becoming clear. Hence, numerous laboratories are pursuing novel compounds targeting the three known histamine receptors found in the brain for various therapeutic indications. Preclinical studies are focusing on three major areas of interest and intense research is mainly oriented towards providing drugs for the treatment of sleep, cognitive and feeding disorders. This commentary is intended to summarize some of the latest findings that suggest functional roles for the interplay between histamine and other neurotransmitter systems, and to propose novel interactions as physiological substrates that may partially underlie some of the behavioral changes observed following manipulation of the histaminergic system.