Histamine Excites Striatal Dopamine D1 and D2 Receptor-Expressing Neurons via Postsynaptic H1 and H2 Receptors

The central histaminergic nervous system, originating from the tuberomammillary nucleus (TMN) of the hypothalamus, widely innervates almost the whole brain, including the basal ganglia. Intriguingly, the histaminergic system is altered in parkinsonian patients. Yet, little is known about the effect and mechanisms of histamine on different types of neurons in the basal ganglia circuitry. Here, by using anterograde tracing, immunostaining, patch clamp recording, and single-cell qPCR techniques, we investigate the histaminergic afferents in the striatum, the major input structure of the basal ganglia, as well as the effect of histamine on the striatal GABAergic medium spiny projection neurons (MSNs). We report a direct histaminergic projection from the hypothalamic TMN to the striatum in rats. Furthermore, histamine exerts a strong postsynaptic excitatory effect on both dopamine D1 and D2 receptor-expressing MSNs. The concentration-response curves and the EC₅₀ values for histamine on these two types of MSNs are similar. In addition, dopamine D1 and D2 receptor-expressing MSNs co-express histamine H1 and H2 receptor mRNAs. Both histamine H1 and H2 receptors are co-localized on dopamine D1 and D2 receptor-expressing MSNs and co-mediate the histamine-induced excitation on the two types of neurons. These results suggest that the histaminergic afferent inputs in the striatum may modulate both dopamine D1 and D2 receptor-expressing MSNs by activation of postsynaptic histamine H1 and H2 receptors and thus serve as an important extrastriatal modulator for biasing the direct and indirect pathways to actively regulate functions of the basal ganglia and participate in the pathogenesis and pathophysiology of basal ganglia diseases.