Parkinson’s Disease (PD) is characterized by an increased production of oxygen free radicals leading to alteration of the cellular constituents and subsequent dopaminergic cell loss within the region of substantia nigra (SN) and ventral tegmental area (VTA). However, it is well known that PD is not only associated with dopaminergic transmission. Involvement of extranigral structures in PD includes the noradrenergic system as well. Post-mortem studies of human brains revealed that neuronal loss associated with PD may proceed and is even greater in the region of locus ceruleus (LC) than SN/ VTA. In PD animal models, the loss of noradrenaline made worse the dopamine nigrostriatal damage and, in opposite, an enhanced noradrenaline level may have a neuroprotective role. The aim of this study was to determine whether genetically evoked, selective loss of noradrenergic neurons may have any long-term, negative impact on the dopaminergic system. We applied the conditional inactivation of the gene encoding transcription factor TIF-IA (essential for the regulation of rRNA synthesis) by the Cre-loxP system to induce the progressive and selective loss of noradrenergic neurons which was achieved by expressing Cre recombinase under dopamine beta-hydroxylase (DBH) promoter. Resulting TIFIADBHCre mice were born at expected rates, viable but showed clear signs of noradrenergic innervations failure e.g. ptosis, reduced locomotor activity, growth retardance and shorten life span. The animals were analyzed at 8 and 12 weeks of age. The selective loss of noradrenergic neurons was confirmed by immunofluorescent staining with the anti-tyrosine hydroxylase (TH) antibody. We observed approx. 90% reduction of TH positive cells in the LC of 8 weeks TIF-IADBHCre mice. The number of TH+ cells was not changed in the region of SN/VTA, neither in 8 nor 12 week old mutants. However, our preliminary data indicate that lack of the noradrenergic transmission may lead to enhanced expression of selected markers associated with neurodegeneration within the region of SN/VTA. Namely, we have found 1.4 fold up-regulation of mRNA encoding for glial fibrillary acidic protein (GFAP) as revealed by quantitative real-time PCR and increased level of oxidative stress shown by immunoblot detection of carbonyl groups by Western Blot in the SN/VTA of 12 weeks TIF-IADBHCre mice compared to control animals. If we provide additional evidences that selective noradrenergic degeneration affects functioning of dopaminergic neurons, TIF-IADBHCre mice may became a valuable, new model for study possible anti-PD treatment at early stages of the disease as dopaminergic neurons in these mice are not directly affected by the mutation. As for today, there are no experimental studies on a possible long-term negative impact of progressive noradrenergic degeneration on other neurotransmitter systems despite of clinically observed concomitant loss of SN/VTA and LC neurons in PD. This study was supported by the grant no 2011/03/B/NZ7/05949 financed by National Science Centre and statutory funds of the Institute of Pharmacology, Polish Academy of Sciences.
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