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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.
Adapted social behavior allows both individual and collective well‑being. At the individual level, it is a hallmark of health. Indeed, virtually all mental health disorders are associated with social deficits. We are interested in understanding the behavioral, neural, and neurochemical bases of social cognition and communication using mouse models. Here, we will review our recent data showing the crucial role of the prefrontal cortex in the organisation of adapted social interaction, the interplay between the cholinergic and the noradrenergic systems for the balance between affiliative interaction, dominance, and control of aggressiveness, and we will discuss the putative role of ultrasonic communication in social interactions in adult animals. We will see the role played by the environment of life and by the context in which interactions take place in healthy individuals and in pathological situations. Together, the data presented will offer a novel focus on the social brain – and social life – of rodents and provide some practical recommendations for future experiments.
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Mirtazapine (MIR)is an antidepressant which enhances noradrenergic and serotonergic 5-HT1A neurotransmission via antagomism of central alpha2 - adrenergic autoreceptors and heteroreceptors.The drugs does not inhibit noradrenaline and serotonin reuptake but blocks the 5-HT2 and 5-HT3 receptors and has high affinity only for central and peripheral histamine H1 receptors.The present study was aimed at determining whether repeated MIR treatment induced adaptive changes in the alpha1 - adrenergic receptors,similar to those reported by us early for tricyclic antidepressants,The experiments were carried out on male mice and rats.MIR was administered at a dose of 10 mg/kg once or repeatedly (twice daily for 14 days).The obtained results showed that MIR administrated repeatedly potentiated the methoxamine-induced exploratory hyperactivity in rats and clonidine- induced aggressiveness in mice,those effects being mediated by alpha1 - adrenergic receptors. MIR given repeatedly (but not acutely)increased the binding (Bmax )of [3H ]prazosin to alpha1 - adrenergic receptors in cerebral cortex,however,the ability of the alpha1 - adrenoceptor agonist phenylephrine to compete for the these sites was not significantly changed.The above results indicate that repeated MIR administration increases the responsiveness of alpha1 - adrenergic system (behavioural and biochemical changes),as tricyclics do.However, the question whether the increased functional responsiveness found in the present study is important for the clinical antidepressant efficacy,remains open.
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