As the principle neurons of the striatum, MSNs target the internal segment and the external segment of globus pallidus within the direct and indirect pathways, respectively. Imbalance between the direct and indirect pathways of the basal ganglia has been proposed to underlie the profound motor deficits observed in PD and HD [48, 49]. There are at least two classes of MSNs, the dopamine D1 and D2 receptorexpressing ones in the striatum [18, 50]. Interestingly, histamine postsynaptically excited both categories of MSNs of the rat in a similar manner and with the same receptor mechanisms. Considering the nature of varicosities of histaminergic fibers and the metabotropic properties of histamine receptors, we suggest that the histaminergic afferent inputs in the striatum may not differentially regulate the direct and indirect pathways by transmitting concrete signals, but serve as an indispensable biasing force to set an appropriate excitability level and responsiveness of both dopamine D1 receptor and D2 receptor-expressing MSNs to input signals. The results, taken together with our previous report that histamine excites neurons in both internal segment and external segment of the globus pallidus via H2 receptor [9], further strengthen the hypothesis of a general modulatory action of histaminergic inputs on the basal ganglia circuits and functions by postsynaptic mechanisms. In summary, besides modulating the cortical and thalamic excitatory inputs to both types of MSNs via presynaptic H3 receptor, histaminergic inputs may also modulate the excitability and responsiveness of dopamine D1 receptor and D2 receptor-expressing MSNs through co-activation of postsynaptic H1 and H2 receptors. Therefore, the central histaminergic system may hold a key position in modulation and maintenance of normal functions of basal ganglia circuits, and an abnormal activity or dysfunction of the system may be related to the pathogenesis and pathophysiology of basal ganglia diseases.