Neurochemical, molecular and behavioral response to pharmacological activation of serotonin system in rats with altered serotonin homeostasis

Kesić, Maja (2016) Neurochemical, molecular and behavioral response to pharmacological activation of serotonin system in rats with altered serotonin homeostasis. Doctoral thesis, Faculty of Science > Department of Biology.

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Abstract

Serotonin transporter (5HT transporter, 5HTT) represents the target molecule of selective serotonin reuptake inhibitors (SSRIs) acting as antidepressant drugs. Although commonly used, these drugs produce a therapeutic effect only in a small number of patients (up to 50 %), and the reasons for that are not known. The association between therapeutic response and 5HTT gene polymorphism has pointed out to possible role of the constitutional serotonin homeostasis in clinical response to SSRI. Using the original animal model, Wistar-Zagreb 5HT rats, whose sublines have constitutional high (high-5HT) or low (low-5HT) of platelet 5HTT activity, we have investigated the relationship between constitutional 5HT homeostasis and responses to SSRI treatment. Following pharmacological activation of 5HT system, induced by single or repeated doses of SSRI fluoxetine, we have compared these sublines with respect to (i) the 5HTT activity and the 5HT levels in the brain and blood, (ii) the expression of 5HTT and 5HT1A receptor genes in the brain, and (iii) the selected behaviors modulated by serotonin. Acute treatment with fluoxetine led to inhibition of platelet 5HTT activity, which was more pronounced in animals from the high-5HT subline, and to increase of plasma 5HT level, which was higher in animals from the low-5HT subline. Chronic administration of the drug caused a significant decrease of platelet serotonin levels, which was higher in animals from the low-5HT subline, and a decrease of plasma 5HT levels, which was higher in animals from the high-5HT subline. The reduction of anxiety-like behavior, along with the increase of exploratory and locomotor activity after chronic treatment with fluoxetine was observed only in animals from the high-5HT subline, and was accompanied by the tendency towards increase of 5HT1A receptor gene expression in hippocampus and the tendency towards increased expression of 5HTT gene in raphe nuclei. On the other hand, in animals from the low-5HT subline, chronic application of fluoxetine led to decrease in 5HTT and 5HT1A receptor mRNA levels and tendency towards decrease in 5HT in the cerebral cortex. he obtained results show that constitutional serotonin homeostasis is an important factor in response to fluoxetine treatment. Furthermore, Wistar-Zagreb 5HT sublines may represent a useful model in studding the neurobiological basis of a different individual response to antidepressants, as well as in evaluating platelets as a peripheral model for predicting the therapeutic response.

Item Type: Thesis (Doctoral thesis)
Keywords: serotonin; serotonin transporter; 5HT1A receptor; anxiety; fluoxetine; Wistar-Zagreb 5HT rats
Supervisor: Čičin-Šain, Lipa and Štefulj, Jasminka
Date: 2016
Number of Pages: 143
Subjects: NATURAL SCIENCES > Biology
Divisions: Faculty of Science > Department of Biology
Depositing User: Grozdana Sirotic
Date Deposited: 14 Oct 2016 10:13
Last Modified: 14 Oct 2016 10:13
URI: http://digre.pmf.unizg.hr/id/eprint/5177

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