The H3 subclass of histamine receptors could mediate the histamine signals in central nervous system (CNS) and peripheral nervous system (PNS). It signals through the inhibition of adenylyl cyclase and displays high constitutive activity which also known as the spontaneous activity in the absence of agonist.

 

It functions as an autoreceptor coupled to Gi proteins to regulates the amount of histamine in the body and as an inhibitory heteroreceptor by inhibiting further synthesis of histamine and regulating the release of other neurotransmitters such as dopamine, acetylcholine and norepinephrine (Protein Data Bank, 2017). The CNS, presynaptic neurons and myenteric plexus are where these receptors widely distributed.

 

In vivo microdialysis has demonstrated that the administration of selective H3-R agonists such as R(-)-α-methylhistamine and imetit reduces the histamine level and its turnover. Administration of H3-R antagonist, in contrast, gives rise to histamine level by enhancing its turnover proved that it serves as an autoreceptor. The H3-R antagonist is widely used as potential therapeutic agents for the treatment of cognitive deficits associated with a variety of CNS diseases including Alzheimer's disease, attention deficit hyperactivity disorder (ADHD) and schizophrenia.