Modulation of histamine H-3 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 th e altered innervation is a consequence of dopamine deficiency. The aim of t he present study was to investigate possible changes in the H-3 receptor sy stem in a well-characterized model of Parkinson's disease - the 6-hydroxydo pamine (6-OHDA) lesioned rats. Histamine immunohistochemistry showed a mino r increase of the fibre density index but we did not find any robust increa se of histaminergic innervation in the ipsilateral substantia nigra on the lesioned side. In situ hybridization showed equal histidine decarboxylase m RNA expression on both sides in the posterior hypothalamus. H-3 receptors w ere labelled with N-alpha-[3H]-methyl histamine dihydrochloride ([H-3] NAMH ). Upregulation of binding to H-3 receptors was found in the substantia nig ra 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 stri atum and substantia nigra on the lesioned side. In situ hybridization of H- 3 receptor mRNA demonstrated region-specific mRNA expression and an increas e of H-3 receptor mRNA in ipsilateral striatum. Thus, the histaminergic sys tem 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 recept or mRNA expression and binding may, for example, modulate GABAergic neurona l activity in dopamine-depleted striatum.