Histamine (2-[4-imidazole]ethylamine) is a low-molecular-weight amine synthesized from L-histidine. It is produced by various cells throughout the body, including central nervous system neurons, gastric mucosa parietal cells, mast cells, basophils and lymphocytes. Histamine is a major biological mediator whose functions include, among many others, regulation of vascular smooth muscle, immune regulation, regulation of sleep-wake cycles and regulation of gastric acid secretion.¹

The biological effects of histamine are mediated through four receptors (H₁-H₄ receptors) all of which belong to the 7-transmembrane domain, G protein-coupled receptor (GPCR) superfamily.

H₃ receptor couples to G_i/G₀ proteins and receptor activation leads to inhibition of adenylate cyclase, activation of the mitogen-activated protein kinase (MAPK) cascade and inhibition of the Na⁺/H⁺ exchanger.^1,2

H₃ receptors are expressed primarily in the central nervous system (CNS) where they are located in presynaptic membranes of histaminergic neurons, where they negatively regulate the synthesis and release of histamine. In addition, H₃ receptors are also located on nonhistaminergic neurons, where they regulate the release of other amines such as dopamine, serotonin, and norepinephrine.^2,3

Based on these studies, a central role for H₃ receptors has been proposed in disorders involving cognition such as attention deficit and hyperactivity disorder (ADHD), Alzheimer disease and Schizophrenia, as well as sleep and energy homeostasis (i.e. obesity) disorders.^2,3