Histamine Modulation of the Basal Ganglia Circuitry in the Motor Symptoms of Parkinson's Disease

Parkinson's disease (PD) is characterized by dopaminergic system dysfunction that results from the degeneration of neurons in the substantia nigra. However, studies suggest that other neurotransmitters, especially histamine, may also play a role in the development of PD.

Numerous studies show that histamine levels in the basal ganglia significantly change in PD pathology, correlating with motor symptoms observed in animal models of PD. Histamine activates H1R or H4R on microglia in the substantia nigra, triggering an inflammatory response and promoting dopaminergic neuron degeneration. Additionally, histamine modulates neuronal excitability and firing activity (firing rate and pattern) by activating H1R, H2R, or H3R on neurons in the basal ganglia nucleus, ultimately impacting normal motor behavior as well as motor symptoms in models of PD.

This review presents the role of histamine and its receptor ligands in the basal ganglia nuclei, along with downstream ion channels linked to histamine receptors that influence immune response, neuronal excitability, and firing activity in PD. It highlights their effects on neuronal firing and their connection to PD motor symptoms. Investigating new ligands targeting basal ganglia histamine receptors and associated ion channels may facilitate the development of novel treatments for PD.