Sex-specific effects of endocannabinoids on behaviour and activity of catecholamine system in hippocampus and medial prefrontal cortex in animal model of depression

[M. Janković]

115 str.

Biološke nauke - Neuroendokrinologija / Biology - Neuroendrocrinology

Mnogi aspekti patofiziologije depresije još nisu dovoljno razjašnjeni, poput ĉinjenice da nesrazmerno više pogaĊa ţene od muškaraca. Endokanabinoidni neurotransmiterski sistem mozga ima vaţnu ulogu u odrţavanju homeostaze organizma tokom stresa i istraţivanja upućuju na njegovu ukljuĉenost u razvoj depresije. Korišćenjem URB597, inhibitora hidrolaze masno-kiselinskih amida, koji svojim dejstvom povećava koliĉinu dostupnog anadamida, ispitivano je dejstvo endokanabinoida na ponašanje nalik depresivnom i anksioznom, koliĉinu kateholamina, enzime njihove sinteze (TH, DBH) i razgradnje (COMT i MAO-A) i kateholaminske receptore, inflamatorni status i aktivaciju MAPK i PI3K/Akt signalnih puteva u medijalnom prefrontalnom korteksu (mPFC) i hipokampusu u animalnom modelu depresije. Pacovi oba pola bili su izloţeni hroniĉnom nepredvidivom stresu (CUS) u periodu od 6 nedelja. Poslednje dve nedelje CUS protokola, ţivotinje su primale URB597 (0.3mg/kg) ili rastvaraĉ iste zapremine. Ponašanje ţivotinja je praćeno primenom testova prinudog plivanja, otvorenog plus lavirinta i testa prepoznavanja novog objekta, dok su neurohemijski parametri ispitivani Western blot i ELISA metodom. Rezultati ove doktorske disertacije pokazali su da je URB597 snaţnije ispoljio antidepresivna i anksiolitiĉka svojstva kod pacova muškog pola, kao i da je pozitivno, polno-specifiĉno uticao na memoriju pacova. URB597 je polno specifiĉno regulisao kateholaminski sistem, MAPK i PI3K/Akt signalni put u mozgu. URB597 je smanjio nivo proinflamatornih citokina u hipokampusu i mPFC ţivotinja oba pola, što doprinosi njegovom pozitivnom dejstvu u ovom modelu depresije. Rezultati ove disertacije omogućavaju bolje razumevanje polnih razlika u patofiziologiji i tretmanu depresije i predstavljaju znaĉajan doprinos u razumevanju modulatornog dejstva endokanabinoida na kateholaminski sistem, MAPK i PI3K signalizaciju u mPFC i hipokampusu.

There are many aspects of patophysiology of depresssion that remain unclear, such as the disproportionate prevalence of depression among women compared to men. The endocannabinoid neurotransmitter system in the brain plays an important role in maintaining homeostasis during stressful events, and research suggests its significance in the development of depression. URB597, a selective inhibitor of fatty acid amide hydrolase that increases the availability of anandamide, was used to analyze the effects of endocannabinoids on depressive-like and anxiety-like behavior, catecholamine levels, enzymes responsible for catecholamine synthesis (TH, DBH), degradation (COMT and MAO-A), catecholamine receptors, inflammatory status, and activation of the MAPK and PI3K/Akt signal pathways in the medial prefrontal cortex (mPFC) and hippocampus in an animal model of depression. Rats of both sexes were expossed to the chronic unpredictable stress (CUS) for 6 weeks. During the last two weeks of the CUS protocol, animals were injected with URB597 (0.3 mg/kg) or the same volume of vehicle. Animal behavior was examined using the forced swim test, elevated plus maze test, and the novel object recognition test, and neurochemical parameters were examined using Western blot and ELISA methods. The results of this PhD dissertation demonstrated that URB597 had stronger antidepressant and anxiolytic effects in male rats, as well as a positive influence on the memory of rats in a sex-specific manner. URB597 regulated the catecholamine system and MAPK and PI3K/Akt signal pathways in the brain in a sex-specific manner. URB597 reduced the levels of proinflammatory cytokines in the hippocampus and mPFC of animals of both sexes, contributing to its positive effects in this model of depression. The results of this thesis allow for a better understanding of sex differences in the pathophysiology and treatment of depression and provide a valuable contribution to understanding the modulatory effects of endocannabinoids on the catecholamine system, MAPK and PI3K signal pathways in the mPFC and hippocampus.

depresija, ponašanje, hroniĉni nepredvidivi stres, FAAH inhibitor URB597, kateholamini, endokanabinoidi, citokini, MAPK signalni put, PI3K/Akt signalni put

depression, behavior, chronic undpredictable stess, FAAH inhibitor URB597, catecholamines, endocannabinoids, cytokines, MAPK signal pathway, PI3K/Akt signal pathway

577.25:577.1(043.3)

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