prikaz prve stranice dokumenta Neurokemijski, molekularni i bihevioralni odgovor na farmakološku aktivaciju serotoninskoga sustava u štakora s promijenjenom homeostazom serotonina
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doctoral thesis
Neurokemijski, molekularni i bihevioralni odgovor na farmakološku aktivaciju serotoninskoga sustava u štakora s promijenjenom homeostazom serotonina
Zagreb: University of Zagreb, Faculty of Science, 2016. urn:nbn:hr:217:404708
Kesić, Maja
University of Zagreb
Faculty of Science
Department of Biology

Institutional repository: Repository of the Faculty of Science

Cite this document

Kesić, M. (2016). Neurokemijski, molekularni i bihevioralni odgovor na farmakološku aktivaciju serotoninskoga sustava u štakora s promijenjenom homeostazom serotonina (Doctoral thesis). Zagreb: University of Zagreb, Faculty of Science. Retrieved from https://urn.nsk.hr/urn:nbn:hr:217:404708

Kesić, Maja. "Neurokemijski, molekularni i bihevioralni odgovor na farmakološku aktivaciju serotoninskoga sustava u štakora s promijenjenom homeostazom serotonina." Doctoral thesis, University of Zagreb, Faculty of Science, 2016. https://urn.nsk.hr/urn:nbn:hr:217:404708

Kesić, Maja. "Neurokemijski, molekularni i bihevioralni odgovor na farmakološku aktivaciju serotoninskoga sustava u štakora s promijenjenom homeostazom serotonina." Doctoral thesis, University of Zagreb, Faculty of Science, 2016. https://urn.nsk.hr/urn:nbn:hr:217:404708

Kesić, M. (2016). 'Neurokemijski, molekularni i bihevioralni odgovor na farmakološku aktivaciju serotoninskoga sustava u štakora s promijenjenom homeostazom serotonina', Doctoral thesis, University of Zagreb, Faculty of Science, accessed 06 January 2025, https://urn.nsk.hr/urn:nbn:hr:217:404708

Kesić M. Neurokemijski, molekularni i bihevioralni odgovor na farmakološku aktivaciju serotoninskoga sustava u štakora s promijenjenom homeostazom serotonina [Doctoral thesis]. Zagreb: University of Zagreb, Faculty of Science; 2016 [cited 2025 January 06] Available at: https://urn.nsk.hr/urn:nbn:hr:217:404708

M. Kesić, "Neurokemijski, molekularni i bihevioralni odgovor na farmakološku aktivaciju serotoninskoga sustava u štakora s promijenjenom homeostazom serotonina", Doctoral thesis, University of Zagreb, Faculty of Science, Zagreb, 2016. Available at: https://urn.nsk.hr/urn:nbn:hr:217:404708

Metadata
TitleNeurokemijski, molekularni i bihevioralni odgovor na farmakološku aktivaciju serotoninskoga sustava u štakora s promijenjenom homeostazom serotonina
Title (english)Neurochemical, molecular and behavioral response to pharmacological activation of serotonin system in rats with altered serotonin homeostasis
AuthorMaja Kesić
MentorLipa Čičin-Šain (mentor)
MentorJasminka Štefulj (sumentor)
Committee memberTatjana Bordukalo-Nikšić (član povjerenstva)
MBZ: 231170
Committee memberDubravka Hranilović (član povjerenstva)
Committee memberAnte Tvrdeić (član povjerenstva)
MBZ: 157335
GranterUniversity of Zagreb
Faculty of Science
(Department of Biology)
Zagreb
Defense date and country2016, Croatia
Scientific / art field,
discipline and subdiscipline		NATURAL SCIENCES
Biology
Universal decimal classification
(UDC)		577 - Biochemistry. Molecular biology. Biophysics
Abstract
Serotoninski prijenosnik (5HT prijenosnik, 5HTT) predstavlja ciljnu molekulu djelovanja antidepresivnih lijekova iz skupine selektivnih inhibitora povratnog unosa serotonina (SSRI). Iako često korišteni, ovi lijekovi ostvaruju terapijski učinak samo kod manjeg broja (do 50 %) bolesnika, a razlozi za to nisu poznati. Nalaz povezanosti terapijskog odgovora s polimorfizmom gena za 5HTT uputio je na moguću ulogu konstitucijske serotoninske homeostaze u kliničkom odgovoru na SSRI. Primjenom originalnog životinjskog modela, Wistar-Zagreb 5HT štakor, čije sublinije imaju konstitucijski pojačanu (5HT-visoki) ili smanjenu (5HT-niski) aktivnost trombocitnog 5HTT, u ovom radu je istražen odnos između konstitucijske 5HT homeostaze i odgovora na tretman SSRI-om. Farmakološka aktivacija 5HT sustava izazvana je jednokratnom ili kroničnom primjenom SSRI-a fluoksetina, a cilj je bio usporediti sublinije s obzirom na učinke fluoksetina na (i) aktivnost 5HTT i razinu 5HT u mozgu i na periferiji, (ii) razinu mRNA za 5HTT i receptor 5HT1A u mozgu te (iii) odabrana ponašanja modulirana serotoninom. Jednokratni tretman fluoksetinom doveo je do inhibicije aktivnosti trombocitnog 5HTT, koja je bila jače izražena kod životinja iz 5HT-visoke sublinije, te do porasta razine plazmatskog 5HT, koji je bio veći kod životinja iz 5HT-niske sublinije. Kronična primjena lijeka dovela je do značajnog pada razine trombocitnog serotonina, koji je bio veći kod životinja iz 5HT-niske sublinije, te do pada plazmatskog serotonina, koji je bio veći kod životinja iz 5HT-visoke sublinije. Smanjenje ponašanja nalik na anksioznost, kao i porast istraživačke i lokomotorne aktivnosti nakon kroničnog tretmana fluoksetinom bilo je prisutno samo kod životinja iz 5HT-visoke sublinije, a praćeno je promjenama u mozgu koje su bile vidljive kao tendencija povećanja ekspresije gena za 5HT1A receptor u hipokampusu te ekspresije gena za 5HTT u regiji jezgara rafe. S druge strane, kod životinja iz 5HT-niske sublinije, kronična primjena fluoksetina dovela je do pada kortikalne ekspresije mRNA za 5HTT i receptor 5HT1A, te tendencije pada razine 5HT u moždanoj kori, dok učinci na ponašanje nisu bili značajni. Rezultati istraživanja pokazuju da je konstitucijska serotoninska homeostaza važan čimbenik odgovora na tretman fluoksetinom. Sublinije Wistar-Zagreb 5HT štakora mogu biti koristan model u istraživanju neurobiološke osnove različitog odgovora pojedinaca na terapiju antidepresivima, kao i za vrednovanje trombocita kao perifernog modela za predviđanje terapijskog odgovora.
Abstract (english)
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. The 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.
Keywords
Keywords (english)
Languagecroatian
URN:NBNurn:nbn:hr:217:404708
Study programmeTitle: Biology
Study programme type: university
Study level: postgraduate
Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija (doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija)
Type of resourceText
File originBorn digital
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Created on2017-05-16 09:13:42