engleski

Wistar Zagreb-5HT rat: a rodent model of constitutive dysregulation of serotonin transporter

Serotonin transporter (5HTT), a monoamine carrier protein, regulates serotonergic signalling via reuptake of serotonin from synaptic cleft into pre-synaptic neuron. Changes in 5HTT signalling are associated with a variety of behaviors and behavior-related disorders which are effectively treated with selective serotonin reuptake inhibitors (SSRIs). Beside in the brain, structurally identical 5HT transporter protein is expressed in peripheral tissues, including blood platelets. Platelets acquire their own serotonergic system similar to serotonergic neurons, but without synthetic enzyme, and could be used for studying some aspects of brain 5HT mechanisms. In our laboratory, the extreme phenotype approach was used to develop, by use of selective breeding, two diverse rat sublines (Cicin-Sain and Jernej, 2010). Platelet serotonin level and velocity of platelet serotonin uptake, which is the main determinant of serotonin level, were applied as selection criteria. Sublines are termed high- and low-5HT rats and constitute original genetic model, Wistar-Zagreb 5HT rats (WZ-5HT rats). Animals from 5HT-sublines are characterized by constitutional up-regulation / down-regulation of platelet 5HTT activity and consequently altered peripheral serotonin homeostasis, as evidenced from diverse studies. One of the findings, the decrease in 5HT uptake after systemic administration of SSRIs, which was more pronounced in high-5HT animals, suggests that differences in central pharmacodynamic response to SSRI could also be expected between sublines. Indeed, animals from high-5HT subline had slightly increased [3H]-citalopram binding sites in several brain regions, and the increase of hippocampal extracellular 5HT after challenge with citalopram was significantly higher also in this subline. On the molecular level, trend for higher 5HTT gene expression in high-5HT animals was observed, but without significance. Notwithstanding, various behavioral studies indicate differences in brain serotonergic signalling between 5HT-sublines. Summary of our neurochemical, molecular and behavioral studies on sublines of Wistar-Zagreb 5HT rat will be presented, focusing to the possibility that our model may represent a useful tool in serotonin transporter research, at both central and peripheral level.

serotonin transporter; platelet; rat

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