Modulation of histamine H3 receptors in the brain of 6-hydroxydopamine-lesioned rats

Parkinson's disease is a major neurological disorder that primarily affects the nigral dopaminergic cells. Nigral histamine innervation is altered in human postmortem Parkinson's disease brains. However, it is not known if the altered innervation is a consequence of dopamine deficiency. The aim of the present study was to investigate possible changes in the H-3 receptor system in a well-characterized model of Parkinson's disease - the 6-hydroxydopamine (6-OHDA) lesioned rats. Histamine immunohistochemistry showed a minor increase of the fibre density index but we did not find any robust increase of histaminergic innervation in the ipsilateral substantia nigra on the lesioned side. In situ hybridization showed equal histidine decarboxylase mRNA expression on both sides in the posterior hypothalamus. H-3 receptors were labelled with N-alpha-[3H]-methyl histamine dihydrochloride ([H-3] NAMH). Upregulation of binding to H-3 receptors was found in the substantia nigra and ventral aspects of striatum on the ipsilateral side. An increase of GTP-gamma-[S-35] binding after H-3 agonist activation was found in the striatum and substantia nigra on the lesioned side. In situ hybridization of H-3 receptor mRNA demonstrated region-specific mRNA expression and an increase of H-3 receptor mRNA in ipsilateral striatum. Thus, the histaminergic system is involved in the pathological process after 6-OHDA lesion of the rat brain at least through H-3 receptor. On the later stages of the neurotoxic damage, less H-3 receptors became functionally active. Increased H-3 receptor mRNA expression and binding may, for example, modulate GABAergic neuronal activity in dopamine-depleted striatum.