The magnificent two: histamine and the H3 receptor as key modulators of striatal circuitry

- Brain region specific signaling of H3R
- Activation of H3R in the striatum is Gi independent.
- Striatal H3R triggers MAPK activation in D1-MSNs and AKT/GSK3β in D2-MSNs.
- Aberrant histaminergic function is a potential cause of tic disorders.
- H3R as a target for treating neuropsychiatric disorders and addictions

Histaminergic dysfunction has been recently linked to tic disorders and to aberrant striatal function. There is a particular interest in the histamine 3 receptor (H3R) due to its clinical implications for treating multiple disorders and its high expression in the brain. Striatal histamine (HA) modulates through the H3R in complex ways the release of striatal neurotransmitters into this brain region. The H3R has been classically described to be coupled to Gi, although there is evidence that revealed that striatal H3R forms heteromers with the dopamine receptors 1 and 2 in the medium spiny neurons (MSNs) than changes this signaling. Moreover, new data described for the first time a complete, segregated and time dependent signaling after H3R activation in the two types of MSNs (D1R-MSNs and D2R-MSNs). The aim of this review is to update the role of HA and H3R in striatal function at a molecular and signaling levels.