engleski

Rat model of constutional upregulation/downregulation of the serotonin transporter

The serotonin transporter (5HTt) regulates 5HT transmission by reuptake of the amine into the presynaptic terminal. Its malfunction has been linked to etiopathogenesis of several neuropsychiatric disorders and it also represents a target for SRI antidepressants. Several 5HT synaptic proteins, including 5HTt, have peripheral expression on blood platelets. This peculiarity of the serotonergic system gave rise to the platelet 5HT model in neurobiolgy and biological psychiatry. Besides clinical studies on platelet 5HTt, the role of this regulatory protein has been studied at the experimental level. Except for mice with targeted disruption of the 5HTt gene there is, to our knowledge, no animal model of constitutional dysregulation of 5HTt. By breeding selection for the extreme values of platelet 5HT levels, we have developed sublines of rats with hyper- and hypo-serotoninemia. Since platelet 5HT content depends directly on its uptake mediated by 5HTt, the selection process has, not unexpectedly, affected 5HTt kinetics. The platelets of the selected animals demonstrated thus upregulation or downregulation of 5HTt, confirmed further by expression studies on mRNA and protein levels. According to the platelet model, a search for the analogous changes in brains of the selectively bred animals was performed. Neurochemical studies have revealed differences in 5HTt function in ventral hippocampus (as measured by microdialysis after citalopram challenge), there were no changes however in 5HT uptake into cortical synaptosomes of untreated animals. Molecular genetic studies demonstrated significant differences in 5HTt mRNA levels in midbrain raphe region. Behavioral studies showed differences in components of 5HT motor syndrome, ethanol consumption and social interaction between sublines. In conclusion, we have developed sublines of rats with constitutional, bidirectional dysregulation of 5HTt and consequent alterations in serotonergic homeostasis in both, periphery and brain.

serotonin transporter; genetical selection; gene expression; behavior

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