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The Journal of Neuroscience, October 6, 2004, 24(40):8704-8710; doi:10.1523/JNEUROSCI.2690-04.2004

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Behavioral/Systems/Cognitive
Histamine H₃ Receptors Inhibit Serotonin Release in Substantia Nigra Pars Reticulata

Sarah Threlfell,¹ Stephanie J. Cragg,¹ Imre Kalló,^2,3 Gergely F. Turi,³ Clive W. Coen,² and Susan A. Greenfield¹

¹Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom, ²School of Biomedical Sciences, King's College London, London SE1 1UL, United Kingdom, and ³Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1450, Hungary

The substantia nigra pars reticulata (SNr) plays a key role in basal ganglia function. Projections from multiple basal ganglia nuclei converge at the SNr to regulate nigrothalamic output. The SNr is also characterized by abundant aminergic input, including dopaminergic dendrites and axons containing 5-hydroxytryptamine (5-HT) or histamine (HA). The functions of HA in the SNr include motor control via HA H₃ receptors (H₃Rs), although the mechanism remains far from elucidated. In Parkinson's disease, there is an increase in H₃Rs and the density of HA-immunoreactive axons in the SN.

We explored the role of H₃Rs in the regulation of 5-HT release in SNr using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in rat midbrain slices. Immunohistochemistry identified a similar distribution for histaminergic and serotonergic processes in the SNr: immunoreactive varicosities were observed in the vicinity of dopaminergic dendrites. Electrically evoked 5-HT release was dependent on extracellular Ca²⁺ and prevented by Na_V⁺-channel blockade. Extracellular 5-HT concentration was enhanced by inhibition of uptake transporters for 5-HT but not dopamine. Selective H₃R agonists (R)-(-)--methyl-histamine or immepip inhibited evoked 5-HT release by up to 60%. This inhibition was prevented by the H₃R antagonist thioperamide but not by the 5-HT_1B receptor antagonist isamoltane. H₃R inhibition of 5-HT release prevailed in the presence of GABA or glutamate receptor antagonists (ionotropic and metabotropic), suggesting minimal involvement of GABA or glutamate synapses. The potent regulation of 5-HT by H₃Rs reported here not only elucidates HA function in the SNr but also raises the possibility of novel targets for basal ganglia therapies.

Key words: histamine; 5-hydroxytryptamine; basal ganglia; substantia nigra; fast-scan cyclic voltammetry; Parkinson's disease

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Received July 7, 2004; revised August 18, 2004; accepted August 20, 2004.

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