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Opposite Functions of Histamine H₁ and H₂ Receptors and H₃ Receptor in Substantia Nigra Pars Reticulata

¹Department of Pharmacology and ²Department of Neurology, University of Tennessee College of Medicine, Memphis, Tennessee

Submitted 12 February 2006; accepted in final form 25 May 2006

The substantia nigra pars reticulata (SNr) is a key basal ganglia output nucleus. Inhibitory outputs from SNr are encoded 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’s disease, histamine innervation and histamine H₃ receptor expression in SNr may be increased. However, the functional consequences of these alterations are not known. In this study, whole cell patch-clamp recordings were used to elucidate the function of different histamine receptors in SNr. Histamine increased SNr inhibitory projection neuron firing frequency and thus 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. By the hyperpolarization, H₃ receptor activation also increased the irregularity of the interspike 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, as a consequence, exert important effects on motor control.

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