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

• Published in: Journal of neurophysiology Vol. 96; no. 3; pp. 1581 - 1591
• Main Authors: Zhou, Fu-Wen, Xu, Jian-Jun, Zhao, Yu, LeDoux, Mark S, Zhou, Fu-Ming
• Format: Journal Article
• Language: English
• Published: United States Am Phys Soc 01.09.2006
• Subjects: Animals; Basal Ganglia - drug effects; Basal Ganglia - physiology; Female; gamma-Aminobutyric Acid - physiology; Histamine - pharmacology; Male; Mice; Mice, Inbred C57BL; Neurons - classification; Neurons - physiology; Patch-Clamp Techniques; Receptors, Histamine H1 - physiology; Receptors, Histamine H2 - physiology; Receptors, Histamine H3 - physiology; Substantia Nigra - physiology
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.00148.2006

1 Department of Pharmacology and 2 Department 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 H 3 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 H 1 and H 2 receptors that induced inward currents and depolarization. In contrast, histamine H 3 receptor activation hyperpolarized and inhibited SNr inhibitory projection neurons, thus decreasing the intensity of basal ganglia output. By the hyperpolarization, H 3 receptor activation also increased the irregularity of the interspike intervals or changed the pattern of SNr inhibitory neuron firing. H 3 receptor–mediated effects were normally dominated by those mediated by H 1 and H 2 receptors. Furthermore, endogenously released histamine provided a tonic, H 1 and H 2 receptor–mediated excitation that helped keep SNr inhibitory projection neurons sufficiently depolarized and spiking regularly. These results suggest that H 1 and H 2 receptors and H 3 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. Address for reprint requests and other correspondence: F.-M. Zhou, Department of Pharmacology, University of Tennessee College of Medicine, Memphis, TN 38163 (E-mail: fzhou3{at}utmem.edu )