Substantia nigra pars reticulata (SNr) is a key basal ganglia output nucleus. The inhibitory output is coded in spike frequency and pattern of the inhibitory SNr projection neurons. SNr output intensity and pattern are often abnormal in movement disorders of basal ganglia origin. In Parkinson disease, histamine innervation and histamine H₃receptor expression in SNr may be increased. However, the functional consequences of these alterations are not known. In this study, whole cell patch clamp recording was used to elucidate the functions of different histamine receptors in SNr. Histamine increased SNr inhibitory projection neuron firing frequency and hence inhibitory output. This effect was mediated by activation of histamine H₁ and H₂ receptors that induced inward currents and depolarization. In contrast, histamine H₃ receptor activation hyperpolarized and inhibited SNr inhibitory projection neurons, thus decreasing the intensity of basal ganglia output. Via the hyperpolarization, H₃ receptor activation also increased the irregularity of the inter-spike intervals or changed the pattern of SNr inhibitory neuron firing. H₃ receptor-mediated effects were normally dominated by those mediated by H₁ and H₂ receptors. Furthermore, endogenously released histamine provided a tonic, H₁ and H₂ receptor-mediated excitation that helped keep SNr inhibitory projection neurons sufficiently depolarized and spiking regularly. These results suggest that H₁ and H₂ receptors and H₃ receptor exert opposite effects on SNr inhibitory projection neurons. Functional balance of these different histamine receptors may contribute to the proper intensity and pattern of basal ganglia output and affect movement control.