TY  - CONF
AU  - Živanović, Ana
AU  - Mitić, Miloš
AU  - Glavonić, Emilija
AU  - Lukić, Iva
AU  - Adžić, Miroslav
AU  - Ivković, Sanja
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11052
AB  - Major depressive disorder (MDD) affects over 300 million people worldwide. The administration of the sub-anaesthetic dose of ketamine, an NMDAr antagonist, was recently approved as highly effective antidepressant whose therapeutic effects are associated with an increase in BDNF levels in the brain. However, lowering the effective dose of ketamine because of its adverse effects is an important goal. We assessed the changes in BDNF levels after the single administration of two subanesthetic doses of ketamine (6mg/kg, Ket6 and 10mg/kg, Ket10) in the chronic unpredictable stress (CUS) mouse model of depression-like behavior in different brain structures. Male C57BL/6J mice exposed to CUS were treated at the postnatal day 70 with either vehicle, Ket6, or Ket10. Following tail suspension test (TST), to assess depressive phenotype at 2- and 7-days post-treatment, animals were sacrificed and the prefrontal cortex (PFC), hippocampus, and striatum were isolated and processed for Western blot analyses. Statistical significance was determined by 1-way ANOVA. Only Ket6 achieved an antidepressant effect that was extinguished at 7 days. Both doses caused a significant increase in BDNF levels in the striatum while neither dose was able to induce BDNF levels in the hippocampus. The increase in BDNF levels in the PFC was observed only 7 days after the treatment and only with Ket10. The increase in BDNF levels was the greatest in the striatum when it correlated with the antidepressive effects of ketamine. Although this increase was sustained for 7 days it did not correlate with the antidepressive behavior which was already extinguished.
PB  - Belgrade : Serbian Neuroscience Society
C3  - 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
T1  - The effect of different subanesthetic doses of ketamine on BDNF levels in different brain structures in the mouse model of depression
SP  - 83
UR  - https://hdl.handle.net/21.15107/rcub_vinar_11052
ER  - 

@conference{
author = "Živanović, Ana and Mitić, Miloš and Glavonić, Emilija and Lukić, Iva and Adžić, Miroslav and Ivković, Sanja",
year = "2023",
abstract = "Major depressive disorder (MDD) affects over 300 million people worldwide. The administration of the sub-anaesthetic dose of ketamine, an NMDAr antagonist, was recently approved as highly effective antidepressant whose therapeutic effects are associated with an increase in BDNF levels in the brain. However, lowering the effective dose of ketamine because of its adverse effects is an important goal. We assessed the changes in BDNF levels after the single administration of two subanesthetic doses of ketamine (6mg/kg, Ket6 and 10mg/kg, Ket10) in the chronic unpredictable stress (CUS) mouse model of depression-like behavior in different brain structures. Male C57BL/6J mice exposed to CUS were treated at the postnatal day 70 with either vehicle, Ket6, or Ket10. Following tail suspension test (TST), to assess depressive phenotype at 2- and 7-days post-treatment, animals were sacrificed and the prefrontal cortex (PFC), hippocampus, and striatum were isolated and processed for Western blot analyses. Statistical significance was determined by 1-way ANOVA. Only Ket6 achieved an antidepressant effect that was extinguished at 7 days. Both doses caused a significant increase in BDNF levels in the striatum while neither dose was able to induce BDNF levels in the hippocampus. The increase in BDNF levels in the PFC was observed only 7 days after the treatment and only with Ket10. The increase in BDNF levels was the greatest in the striatum when it correlated with the antidepressive effects of ketamine. Although this increase was sustained for 7 days it did not correlate with the antidepressive behavior which was already extinguished.",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade",
title = "The effect of different subanesthetic doses of ketamine on BDNF levels in different brain structures in the mouse model of depression",
pages = "83",
url = "https://hdl.handle.net/21.15107/rcub_vinar_11052"
}

Živanović, A., Mitić, M., Glavonić, E., Lukić, I., Adžić, M.,& Ivković, S.. (2023). The effect of different subanesthetic doses of ketamine on BDNF levels in different brain structures in the mouse model of depression. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
Belgrade : Serbian Neuroscience Society., 83.
https://hdl.handle.net/21.15107/rcub_vinar_11052

Živanović A, Mitić M, Glavonić E, Lukić I, Adžić M, Ivković S. The effect of different subanesthetic doses of ketamine on BDNF levels in different brain structures in the mouse model of depression. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade. 2023;:83.
https://hdl.handle.net/21.15107/rcub_vinar_11052 .

Živanović, Ana, Mitić, Miloš, Glavonić, Emilija, Lukić, Iva, Adžić, Miroslav, Ivković, Sanja, "The effect of different subanesthetic doses of ketamine on BDNF levels in different brain structures in the mouse model of depression" in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade (2023):83,
https://hdl.handle.net/21.15107/rcub_vinar_11052 .

TY  - CONF
AU  - Glavonić, Emilija
AU  - Aleksić, Minja
AU  - Francija, Ester
AU  - Mitić, Miloš
AU  - Lukić, Iva
AU  - Ivković, Sanja
AU  - Adžić, Miroslav
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11051
AB  - Adolescence is a developmental stage characterized by impaired fear extinction learning, which is a significant contributing factor for the high incidence of fearrelated disorders observed across this period. Ketamine is a noncompetitive N-methyl D-aspartate receptor antagonist that targets glutamatergic transmission and mammalian target of rapamycin (mTOR) signaling pathway, synaptic plasticity mediators known to be involved in fear extinction processes. Therefore, we aimed to explore ketamine’s potential to boost fear extinction of adolescent males, as well as to identify the associated molecular mechanisms. Adolescent male mice (C57BL/6) received an i.p. ketamine injection (10 mg/kg) 1h prior to each cued fear extinction session for 4 consecutive days. Protein expression levels of synaptic plasticity markers in hippocampal synaptosomal fractions were subsequently detected by Western blot analysis. Our results revealed that ketamine significantly improved overall fear extinction learning, as well as extinction memory consolidation/retention. Our data also showed that ketamine upregulated protein kinase B (Akt), mTOR and glutamate receptor 1 (GluR1) protein levels in the hippocampus. Interestingly, we detected no changes in the levels of extracellular signal-regulated kinase 1/2. These results suggest that ketamine ameliorates longterm fear extinction of adolescent males via hippocampal Akt-mTOR-GluR1 signaling, highlighting this pathway as an important therapeutic target for improving extinction learning in the adolescent population.
PB  - Belgrade : Serbian Neuroscience Society
C3  - 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
T1  - Ketamine ameliorates fear extinction learning in adolescent males via hippocampal mTOR signaling
SP  - 82
UR  - https://hdl.handle.net/21.15107/rcub_vinar_11051
ER  - 

@conference{
author = "Glavonić, Emilija and Aleksić, Minja and Francija, Ester and Mitić, Miloš and Lukić, Iva and Ivković, Sanja and Adžić, Miroslav",
year = "2023",
abstract = "Adolescence is a developmental stage characterized by impaired fear extinction learning, which is a significant contributing factor for the high incidence of fearrelated disorders observed across this period. Ketamine is a noncompetitive N-methyl D-aspartate receptor antagonist that targets glutamatergic transmission and mammalian target of rapamycin (mTOR) signaling pathway, synaptic plasticity mediators known to be involved in fear extinction processes. Therefore, we aimed to explore ketamine’s potential to boost fear extinction of adolescent males, as well as to identify the associated molecular mechanisms. Adolescent male mice (C57BL/6) received an i.p. ketamine injection (10 mg/kg) 1h prior to each cued fear extinction session for 4 consecutive days. Protein expression levels of synaptic plasticity markers in hippocampal synaptosomal fractions were subsequently detected by Western blot analysis. Our results revealed that ketamine significantly improved overall fear extinction learning, as well as extinction memory consolidation/retention. Our data also showed that ketamine upregulated protein kinase B (Akt), mTOR and glutamate receptor 1 (GluR1) protein levels in the hippocampus. Interestingly, we detected no changes in the levels of extracellular signal-regulated kinase 1/2. These results suggest that ketamine ameliorates longterm fear extinction of adolescent males via hippocampal Akt-mTOR-GluR1 signaling, highlighting this pathway as an important therapeutic target for improving extinction learning in the adolescent population.",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade",
title = "Ketamine ameliorates fear extinction learning in adolescent males via hippocampal mTOR signaling",
pages = "82",
url = "https://hdl.handle.net/21.15107/rcub_vinar_11051"
}

Glavonić, E., Aleksić, M., Francija, E., Mitić, M., Lukić, I., Ivković, S.,& Adžić, M.. (2023). Ketamine ameliorates fear extinction learning in adolescent males via hippocampal mTOR signaling. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
Belgrade : Serbian Neuroscience Society., 82.
https://hdl.handle.net/21.15107/rcub_vinar_11051

Glavonić E, Aleksić M, Francija E, Mitić M, Lukić I, Ivković S, Adžić M. Ketamine ameliorates fear extinction learning in adolescent males via hippocampal mTOR signaling. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade. 2023;:82.
https://hdl.handle.net/21.15107/rcub_vinar_11051 .

Glavonić, Emilija, Aleksić, Minja, Francija, Ester, Mitić, Miloš, Lukić, Iva, Ivković, Sanja, Adžić, Miroslav, "Ketamine ameliorates fear extinction learning in adolescent males via hippocampal mTOR signaling" in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade (2023):82,
https://hdl.handle.net/21.15107/rcub_vinar_11051 .

TY  - CONF
AU  - Lukić, Iva
AU  - Mitić, Miloš
AU  - Pajović, Milica
AU  - Glavonić, Emilija
AU  - Živanović, Ana
AU  - Aleksić, Minja
AU  - Ivković, Sanja
AU  - Elliot, Evan
AU  - Adžić, Miroslav
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11045
AB  - There is accumulating evidence demonstrating effects of gastrointestinal microbiota on brain function and behavior, including depressive behavior. We have demonstrated that antidepressants, the main drugs used for alleviating depression, affect gut microbiota composition as well, and in this way partly contribute to improvement of depressive symptoms. Specifically, our results showed that several types of antidepressants reduced abundance of bacterial genera Ruminococcus, while supplementation with R. flavefaciens diminished antidepressant-induced decrease of depressive behavior. Treatment with R. flavefaciens affected cortical gene networks, up-regulating genes involved in mitochondrial oxidative phosphorylation, while down-regulating genes involved in neuronal plasticity, suggesting a mechanism for microbial regulation of antidepressant treatment efficiency. In further studies, we are aiming to delineate the role of gut microbiota in conveying the long-term effects of adolescent stress on development of anxiety and depressive behavior.
PB  - Belgrade : Serbian Neuroscience Society
C3  - 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
T1  - The role of gut microbiota in depressive behavior and the effects of antidepressants
SP  - 44
UR  - https://hdl.handle.net/21.15107/rcub_vinar_11045
ER  - 

@conference{
author = "Lukić, Iva and Mitić, Miloš and Pajović, Milica and Glavonić, Emilija and Živanović, Ana and Aleksić, Minja and Ivković, Sanja and Elliot, Evan and Adžić, Miroslav",
year = "2023",
abstract = "There is accumulating evidence demonstrating effects of gastrointestinal microbiota on brain function and behavior, including depressive behavior. We have demonstrated that antidepressants, the main drugs used for alleviating depression, affect gut microbiota composition as well, and in this way partly contribute to improvement of depressive symptoms. Specifically, our results showed that several types of antidepressants reduced abundance of bacterial genera Ruminococcus, while supplementation with R. flavefaciens diminished antidepressant-induced decrease of depressive behavior. Treatment with R. flavefaciens affected cortical gene networks, up-regulating genes involved in mitochondrial oxidative phosphorylation, while down-regulating genes involved in neuronal plasticity, suggesting a mechanism for microbial regulation of antidepressant treatment efficiency. In further studies, we are aiming to delineate the role of gut microbiota in conveying the long-term effects of adolescent stress on development of anxiety and depressive behavior.",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade",
title = "The role of gut microbiota in depressive behavior and the effects of antidepressants",
pages = "44",
url = "https://hdl.handle.net/21.15107/rcub_vinar_11045"
}

Lukić, I., Mitić, M., Pajović, M., Glavonić, E., Živanović, A., Aleksić, M., Ivković, S., Elliot, E.,& Adžić, M.. (2023). The role of gut microbiota in depressive behavior and the effects of antidepressants. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
Belgrade : Serbian Neuroscience Society., 44.
https://hdl.handle.net/21.15107/rcub_vinar_11045

Lukić I, Mitić M, Pajović M, Glavonić E, Živanović A, Aleksić M, Ivković S, Elliot E, Adžić M. The role of gut microbiota in depressive behavior and the effects of antidepressants. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade. 2023;:44.
https://hdl.handle.net/21.15107/rcub_vinar_11045 .

Lukić, Iva, Mitić, Miloš, Pajović, Milica, Glavonić, Emilija, Živanović, Ana, Aleksić, Minja, Ivković, Sanja, Elliot, Evan, Adžić, Miroslav, "The role of gut microbiota in depressive behavior and the effects of antidepressants" in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade (2023):44,
https://hdl.handle.net/21.15107/rcub_vinar_11045 .

TY  - CONF
AU  - Mitić, Miloš
AU  - Lukić, Iva
AU  - Glavonić, Emilija
AU  - Živanović, Ana
AU  - Mijović, Milica
AU  - Ivković, Sanja
AU  - Adžić, Miroslav
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11054
AB  - Adolescence is a critical period for neurodevelopment, and exposure to chronic stress during this stage can have long-lasting effects on physiological systems and mental health, particularly on depression. Recent studies report that stress affects the gutbrain axis, leading to changes in gut morphology and motility, nutrient absorption, and gut microbiome, which can be associated with development of depression. We investigated the impact of chronic unpredictable stress (CUS) in adolescence on depressive-like behavior and colon in adult mice. Male C57BL/6 mice were exposed to CUS, including different daily stressors such as social isolation, forced swim, and restraint stress, and others, during postnatal days 28-40. Control mice were housed under standard conditions. Behavioral assessments were conducted during adulthood (postnatal day 70), to evaluate depressive-like behavior. Alterations in mice colon were assessed by histopathological analysis. Our results revealed that mice exposed to CUS during adolescence have disrupted colon, including loss of colonic crypts and significantly increased presence of mucosa and submucosa in respect to controls. Changes in colon were associated with increased depressive-like behavior in CUS-mice compared to control mice. These findings suggest that CUS experienced in adolescence can disrupt colon morphology that is associated with depressive phenotype in adult mice, highlighting the importance of understanding the long-term consequences of chronic stress during this critical period of development as a potential risk for development of depression. Further research is needed to elucidate the underlying mechanisms and potential therapeutic interventions to mitigate the effects of stress on mental health and gut function
PB  - Belgrade : Serbian Neurocardiological Society
C3  - 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
T1  - Chronic unpredictable stress in adolescence causes disruption of colon morphology that is associated with depressive phenotype in adult mice
SP  - 85
UR  - https://hdl.handle.net/21.15107/rcub_vinar_11054
ER  - 

@conference{
author = "Mitić, Miloš and Lukić, Iva and Glavonić, Emilija and Živanović, Ana and Mijović, Milica and Ivković, Sanja and Adžić, Miroslav",
year = "2023",
abstract = "Adolescence is a critical period for neurodevelopment, and exposure to chronic stress during this stage can have long-lasting effects on physiological systems and mental health, particularly on depression. Recent studies report that stress affects the gutbrain axis, leading to changes in gut morphology and motility, nutrient absorption, and gut microbiome, which can be associated with development of depression. We investigated the impact of chronic unpredictable stress (CUS) in adolescence on depressive-like behavior and colon in adult mice. Male C57BL/6 mice were exposed to CUS, including different daily stressors such as social isolation, forced swim, and restraint stress, and others, during postnatal days 28-40. Control mice were housed under standard conditions. Behavioral assessments were conducted during adulthood (postnatal day 70), to evaluate depressive-like behavior. Alterations in mice colon were assessed by histopathological analysis. Our results revealed that mice exposed to CUS during adolescence have disrupted colon, including loss of colonic crypts and significantly increased presence of mucosa and submucosa in respect to controls. Changes in colon were associated with increased depressive-like behavior in CUS-mice compared to control mice. These findings suggest that CUS experienced in adolescence can disrupt colon morphology that is associated with depressive phenotype in adult mice, highlighting the importance of understanding the long-term consequences of chronic stress during this critical period of development as a potential risk for development of depression. Further research is needed to elucidate the underlying mechanisms and potential therapeutic interventions to mitigate the effects of stress on mental health and gut function",
publisher = "Belgrade : Serbian Neurocardiological Society",
journal = "8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade",
title = "Chronic unpredictable stress in adolescence causes disruption of colon morphology that is associated with depressive phenotype in adult mice",
pages = "85",
url = "https://hdl.handle.net/21.15107/rcub_vinar_11054"
}

Mitić, M., Lukić, I., Glavonić, E., Živanović, A., Mijović, M., Ivković, S.,& Adžić, M.. (2023). Chronic unpredictable stress in adolescence causes disruption of colon morphology that is associated with depressive phenotype in adult mice. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
Belgrade : Serbian Neurocardiological Society., 85.
https://hdl.handle.net/21.15107/rcub_vinar_11054

Mitić M, Lukić I, Glavonić E, Živanović A, Mijović M, Ivković S, Adžić M. Chronic unpredictable stress in adolescence causes disruption of colon morphology that is associated with depressive phenotype in adult mice. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade. 2023;:85.
https://hdl.handle.net/21.15107/rcub_vinar_11054 .

Mitić, Miloš, Lukić, Iva, Glavonić, Emilija, Živanović, Ana, Mijović, Milica, Ivković, Sanja, Adžić, Miroslav, "Chronic unpredictable stress in adolescence causes disruption of colon morphology that is associated with depressive phenotype in adult mice" in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade (2023):85,
https://hdl.handle.net/21.15107/rcub_vinar_11054 .

TY  - JOUR
AU  - Adžić, Miroslav
AU  - Lukić, Iva
AU  - Mitić, Miloš
AU  - Glavonić, Emilija
AU  - Dragićević, Nina
AU  - Ivković, Sanja
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11044
AB  - Major depressive disorder (MDD) afflicts approximately 5 % of the world population, and about 30–50 % of patients who receive classical antidepressant medications do not achieve complete remission (treatment resistant depressive patients). Emerging evidence suggests that targeting opioid receptors mu (MOP), kappa (KOP), delta (DOP), and the nociceptin/orphanin FQ receptor (NOP) may yield effective therapeutics for stress-related psychiatric disorders. As depression and pain exhibit significant overlap in their clinical manifestations and molecular mechanisms involved, it is not a surprise that opioids, historically used to alleviate pain, emerged as promising and effective therapeutic options in the treatment of depression. The opioid signaling is dysregulated in depression and numerous preclinical studies and clinical trials strongly suggest that opioid modulation can serve as either an adjuvant or even an alternative to classical monoaminergic antidepressants. Importantly, some classical antidepressants require the opioid receptor modulation to exert their antidepressant effects. Finally, ketamine, a well-known anesthetic whose extremely efficient antidepressant effects were recently discovered, was shown to mediate its antidepressant effects via the endogenous opioid system. Thus, although opioid system modulation is a promising therapeutical venue in the treatment of depression further research is warranted to fully understand the benefits and weaknesses of such approach.
T2  - Life Sciences
T2  - Life SciencesLife Sciences
T1  - Contribution of the opioid system to depression and to the therapeutic effects of classical antidepressants and ketamine
VL  - 326
SP  - 121803
DO  - 10.1016/j.lfs.2023.121803
ER  - 

@article{
author = "Adžić, Miroslav and Lukić, Iva and Mitić, Miloš and Glavonić, Emilija and Dragićević, Nina and Ivković, Sanja",
year = "2023",
abstract = "Major depressive disorder (MDD) afflicts approximately 5 % of the world population, and about 30–50 % of patients who receive classical antidepressant medications do not achieve complete remission (treatment resistant depressive patients). Emerging evidence suggests that targeting opioid receptors mu (MOP), kappa (KOP), delta (DOP), and the nociceptin/orphanin FQ receptor (NOP) may yield effective therapeutics for stress-related psychiatric disorders. As depression and pain exhibit significant overlap in their clinical manifestations and molecular mechanisms involved, it is not a surprise that opioids, historically used to alleviate pain, emerged as promising and effective therapeutic options in the treatment of depression. The opioid signaling is dysregulated in depression and numerous preclinical studies and clinical trials strongly suggest that opioid modulation can serve as either an adjuvant or even an alternative to classical monoaminergic antidepressants. Importantly, some classical antidepressants require the opioid receptor modulation to exert their antidepressant effects. Finally, ketamine, a well-known anesthetic whose extremely efficient antidepressant effects were recently discovered, was shown to mediate its antidepressant effects via the endogenous opioid system. Thus, although opioid system modulation is a promising therapeutical venue in the treatment of depression further research is warranted to fully understand the benefits and weaknesses of such approach.",
journal = "Life Sciences, Life SciencesLife Sciences",
title = "Contribution of the opioid system to depression and to the therapeutic effects of classical antidepressants and ketamine",
volume = "326",
pages = "121803",
doi = "10.1016/j.lfs.2023.121803"
}

Adžić, M., Lukić, I., Mitić, M., Glavonić, E., Dragićević, N.,& Ivković, S.. (2023). Contribution of the opioid system to depression and to the therapeutic effects of classical antidepressants and ketamine. in Life Sciences, 326, 121803.
https://doi.org/10.1016/j.lfs.2023.121803

Adžić M, Lukić I, Mitić M, Glavonić E, Dragićević N, Ivković S. Contribution of the opioid system to depression and to the therapeutic effects of classical antidepressants and ketamine. in Life Sciences. 2023;326:121803.
doi:10.1016/j.lfs.2023.121803 .

Adžić, Miroslav, Lukić, Iva, Mitić, Miloš, Glavonić, Emilija, Dragićević, Nina, Ivković, Sanja, "Contribution of the opioid system to depression and to the therapeutic effects of classical antidepressants and ketamine" in Life Sciences, 326 (2023):121803,
https://doi.org/10.1016/j.lfs.2023.121803 . .

TY  - JOUR
AU  - Glavonić, Emilija
AU  - Mitić, Miloš
AU  - Francija, Ester
AU  - Petrović, Zorica
AU  - Adžić, Miroslav
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10514
AB  - Adolescence is a key phase of development for perturbations in fear extinction, with inability to adequately manage fear a potent factor for developing psychiatric disorders in adulthood. However, while behavioral correlates of adolescent fear regulation are established to a degree, molecular mediators of extinction learning in adolescence remain largely unknown. In this study, we observed fear acquisition and fear extinction (across 4 and 7 days) of adolescent and adult mice of both sexes and investigated how hippocampal levels of different plasticity markers relate to extinction learning. While fear was acquired evenly in males and females of both ages, fear extinction was found to be impaired in adolescent males. We also observed lower levels of GluA1, GLUN2A and GLUN2B subunits in male adolescents following fear acquisition, with an increase in their expression, as well as the activity of Erk-mTOR pathway over subsequent extinction sessions, which was paralleled with improved extinction learning. On the other hand, we detected no changes in plasticity-related proteins after fear acquisition in females, with alterations in GluA1, GluA4 and GLUN2B levels across fear extinction sessions. Additionally, we did not discern any pattern regarding the Erk-mTOR activity in female mice associated with their extinction performance. Overall, our research identifies sex-specific synaptic properties in the hippocampus that underlie developmentally regulated differences in fear extinction learning. We also point out hippocampal NMDA-Erk-mTOR signaling as the driving force behind successful fear extinction in male adolescents, highlighting this pathway as a potential therapeutic target for fear-related disorders in the adolescent population. © 2022 The Authors
T2  - Brain Research Bulletin
T1  - Sex-specific role of hippocampal NMDA-Erk-mTOR signaling in fear extinction of adolescent mice
VL  - 192
SP  - 156
EP  - 167
DO  - 10.1016/j.brainresbull.2022.11.011
ER  - 

@article{
author = "Glavonić, Emilija and Mitić, Miloš and Francija, Ester and Petrović, Zorica and Adžić, Miroslav",
year = "2023",
abstract = "Adolescence is a key phase of development for perturbations in fear extinction, with inability to adequately manage fear a potent factor for developing psychiatric disorders in adulthood. However, while behavioral correlates of adolescent fear regulation are established to a degree, molecular mediators of extinction learning in adolescence remain largely unknown. In this study, we observed fear acquisition and fear extinction (across 4 and 7 days) of adolescent and adult mice of both sexes and investigated how hippocampal levels of different plasticity markers relate to extinction learning. While fear was acquired evenly in males and females of both ages, fear extinction was found to be impaired in adolescent males. We also observed lower levels of GluA1, GLUN2A and GLUN2B subunits in male adolescents following fear acquisition, with an increase in their expression, as well as the activity of Erk-mTOR pathway over subsequent extinction sessions, which was paralleled with improved extinction learning. On the other hand, we detected no changes in plasticity-related proteins after fear acquisition in females, with alterations in GluA1, GluA4 and GLUN2B levels across fear extinction sessions. Additionally, we did not discern any pattern regarding the Erk-mTOR activity in female mice associated with their extinction performance. Overall, our research identifies sex-specific synaptic properties in the hippocampus that underlie developmentally regulated differences in fear extinction learning. We also point out hippocampal NMDA-Erk-mTOR signaling as the driving force behind successful fear extinction in male adolescents, highlighting this pathway as a potential therapeutic target for fear-related disorders in the adolescent population. © 2022 The Authors",
journal = "Brain Research Bulletin",
title = "Sex-specific role of hippocampal NMDA-Erk-mTOR signaling in fear extinction of adolescent mice",
volume = "192",
pages = "156-167",
doi = "10.1016/j.brainresbull.2022.11.011"
}

Glavonić, E., Mitić, M., Francija, E., Petrović, Z.,& Adžić, M.. (2023). Sex-specific role of hippocampal NMDA-Erk-mTOR signaling in fear extinction of adolescent mice. in Brain Research Bulletin, 192, 156-167.
https://doi.org/10.1016/j.brainresbull.2022.11.011

Glavonić E, Mitić M, Francija E, Petrović Z, Adžić M. Sex-specific role of hippocampal NMDA-Erk-mTOR signaling in fear extinction of adolescent mice. in Brain Research Bulletin. 2023;192:156-167.
doi:10.1016/j.brainresbull.2022.11.011 .

Glavonić, Emilija, Mitić, Miloš, Francija, Ester, Petrović, Zorica, Adžić, Miroslav, "Sex-specific role of hippocampal NMDA-Erk-mTOR signaling in fear extinction of adolescent mice" in Brain Research Bulletin, 192 (2023):156-167,
https://doi.org/10.1016/j.brainresbull.2022.11.011 . .

TY  - JOUR
AU  - Glavonić, Emilija
AU  - Mitić, Miloš
AU  - Adžić, Miroslav
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10165
AB  - Fear-related disorders, mainly phobias and post-traumatic stress disorder, are highly prevalent, debilitating disorders that pose a significant public health problem. They are characterized by aberrant processing of aversive experiences and dysregulated fear extinction, leading to excessive expression of fear and diminished quality of life. The gold standard for treating fear-related disorders is extinction-based exposure therapy (ET), shown to be ineffective for up to 35% of subjects. Moreover, ET combined with traditional pharmacological treatments for fear-related disorders, such as selective serotonin reuptake inhibitors, offers no further advantage to patients. This prompted the search for ways to improve ET outcomes, with current research focused on pharmacological agents that can augment ET by strengthening fear extinction learning. Hallucinogenic drugs promote reprocessing of fear-imbued memories and induce positive mood and openness, relieving anxiety and enabling the necessary emotional engagement during psychotherapeutic interventions. Mechanistically, hallucinogens induce dynamic structural and functional neuroplastic changes across the fear extinction circuitry and temper amygdala's hyperreactivity to threat-related stimuli, effectively mitigating one of the hallmarks of fear-related disorders. This paper provides the first comprehensive review of hallucinogens' potential to alleviate symptoms of fear-related disorders by focusing on their effects on fear extinction and the underlying molecular mechanisms. We overview both preclinical and clinical studies and emphasize the advantages of hallucinogenic drugs over current first-line treatments. We highlight 3,4-methylenedioxymethamphetamine and ketamine as the most effective therapeutics for fear-related disorders and discuss the potential molecular mechanisms responsible for their potency with implications for improving hallucinogen-assisted psychotherapy.
T2  - Journal of Neuroscience Research
T1  - Hallucinogenic drugs and their potential for treating fear-related disorders: Through the lens of fear extinction
VL  - 100
IS  - 4
SP  - 947
EP  - 969
DO  - 10.1002/jnr.25017
ER  - 

@article{
author = "Glavonić, Emilija and Mitić, Miloš and Adžić, Miroslav",
year = "2022",
abstract = "Fear-related disorders, mainly phobias and post-traumatic stress disorder, are highly prevalent, debilitating disorders that pose a significant public health problem. They are characterized by aberrant processing of aversive experiences and dysregulated fear extinction, leading to excessive expression of fear and diminished quality of life. The gold standard for treating fear-related disorders is extinction-based exposure therapy (ET), shown to be ineffective for up to 35% of subjects. Moreover, ET combined with traditional pharmacological treatments for fear-related disorders, such as selective serotonin reuptake inhibitors, offers no further advantage to patients. This prompted the search for ways to improve ET outcomes, with current research focused on pharmacological agents that can augment ET by strengthening fear extinction learning. Hallucinogenic drugs promote reprocessing of fear-imbued memories and induce positive mood and openness, relieving anxiety and enabling the necessary emotional engagement during psychotherapeutic interventions. Mechanistically, hallucinogens induce dynamic structural and functional neuroplastic changes across the fear extinction circuitry and temper amygdala's hyperreactivity to threat-related stimuli, effectively mitigating one of the hallmarks of fear-related disorders. This paper provides the first comprehensive review of hallucinogens' potential to alleviate symptoms of fear-related disorders by focusing on their effects on fear extinction and the underlying molecular mechanisms. We overview both preclinical and clinical studies and emphasize the advantages of hallucinogenic drugs over current first-line treatments. We highlight 3,4-methylenedioxymethamphetamine and ketamine as the most effective therapeutics for fear-related disorders and discuss the potential molecular mechanisms responsible for their potency with implications for improving hallucinogen-assisted psychotherapy.",
journal = "Journal of Neuroscience Research",
title = "Hallucinogenic drugs and their potential for treating fear-related disorders: Through the lens of fear extinction",
volume = "100",
number = "4",
pages = "947-969",
doi = "10.1002/jnr.25017"
}

Glavonić, E., Mitić, M.,& Adžić, M.. (2022). Hallucinogenic drugs and their potential for treating fear-related disorders: Through the lens of fear extinction. in Journal of Neuroscience Research, 100(4), 947-969.
https://doi.org/10.1002/jnr.25017

Glavonić E, Mitić M, Adžić M. Hallucinogenic drugs and their potential for treating fear-related disorders: Through the lens of fear extinction. in Journal of Neuroscience Research. 2022;100(4):947-969.
doi:10.1002/jnr.25017 .

Glavonić, Emilija, Mitić, Miloš, Adžić, Miroslav, "Hallucinogenic drugs and their potential for treating fear-related disorders: Through the lens of fear extinction" in Journal of Neuroscience Research, 100, no. 4 (2022):947-969,
https://doi.org/10.1002/jnr.25017 . .

TY  - JOUR
AU  - Adžić, Miroslav
AU  - Glavonić, Emilija
AU  - Nešić, Milica J.
AU  - Milosavljević, Minja
AU  - Mihaljević, Marina
AU  - Petrović, Zorica D.
AU  - Pavlović, Zorana
AU  - Brkić, Željka
AU  - Francija, Ester
AU  - Soldatović, Ivan A.
AU  - Mitić, Miloš
AU  - Radulović, Jelena
AU  - Marić, Nađa P.
PY  - 2019
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8010
AB  - Childhood trauma (CT) increases the risk for psychopathology through disturbed acquisition and extinction of fear. The effects of CT are mediated by abnormalities of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor (GR). Since, the alterations in GRα translational isoforms have been documented in psychiatric disorders we sought to: 1) explore whether multiple GRα isoforms in the human peripheral blood mononuclear cells of two independent cohorts (whole cell n = 40; and nuclear extracts n = 43, adult subjects) mediate the effect of CT on negative affectivity (NA) measured by Depression, Anxiety and Stress Scales (DASS), and 2) examine their role/function during fear extinction in the animal model. In multiple regression analysis, CT, nuclear 40-kDa GRα their interactions and FKBP5 explained 22%–35% of variance in DASS scores. Structural equation modeling showed that CT had a significant direct effect on 40-kDa and DASS in both cohorts, and on the nuclear 25-kDa GRα. The association between 40-kDa and total DASS was significantly mediated by nuclear FKBP5, whereas on DASS anxiety, over FKBP5 in both cohorts and nuclear full length GRα. Nuclear 40-kDa GRα and its interaction with CT had a significant direct effect on DASS anxiety. In mice, the successful extinction learning was followed by nuclear translocation of 40-kDa GRα and induction of BDNF exon IV expression. Our data revealed that the association between CT and adult NA in non-clinical subjects is mediated by the GRα translational isoforms, in particular 40-kDa GRα and emphasized its role in fear extinction and neural plasticity. © 2018 Elsevier Inc.
T2  - Progress in Neuro-Psychopharmacology and Biological Psychiatry
T1  - Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states
VL  - 90
SP  - 288
EP  - 299
DO  - 10.1016/j.pnpbp.2018.12.011
ER  - 

@article{
author = "Adžić, Miroslav and Glavonić, Emilija and Nešić, Milica J. and Milosavljević, Minja and Mihaljević, Marina and Petrović, Zorica D. and Pavlović, Zorana and Brkić, Željka and Francija, Ester and Soldatović, Ivan A. and Mitić, Miloš and Radulović, Jelena and Marić, Nađa P.",
year = "2019",
abstract = "Childhood trauma (CT) increases the risk for psychopathology through disturbed acquisition and extinction of fear. The effects of CT are mediated by abnormalities of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor (GR). Since, the alterations in GRα translational isoforms have been documented in psychiatric disorders we sought to: 1) explore whether multiple GRα isoforms in the human peripheral blood mononuclear cells of two independent cohorts (whole cell n = 40; and nuclear extracts n = 43, adult subjects) mediate the effect of CT on negative affectivity (NA) measured by Depression, Anxiety and Stress Scales (DASS), and 2) examine their role/function during fear extinction in the animal model. In multiple regression analysis, CT, nuclear 40-kDa GRα their interactions and FKBP5 explained 22%–35% of variance in DASS scores. Structural equation modeling showed that CT had a significant direct effect on 40-kDa and DASS in both cohorts, and on the nuclear 25-kDa GRα. The association between 40-kDa and total DASS was significantly mediated by nuclear FKBP5, whereas on DASS anxiety, over FKBP5 in both cohorts and nuclear full length GRα. Nuclear 40-kDa GRα and its interaction with CT had a significant direct effect on DASS anxiety. In mice, the successful extinction learning was followed by nuclear translocation of 40-kDa GRα and induction of BDNF exon IV expression. Our data revealed that the association between CT and adult NA in non-clinical subjects is mediated by the GRα translational isoforms, in particular 40-kDa GRα and emphasized its role in fear extinction and neural plasticity. © 2018 Elsevier Inc.",
journal = "Progress in Neuro-Psychopharmacology and Biological Psychiatry",
title = "Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states",
volume = "90",
pages = "288-299",
doi = "10.1016/j.pnpbp.2018.12.011"
}

Adžić, M., Glavonić, E., Nešić, M. J., Milosavljević, M., Mihaljević, M., Petrović, Z. D., Pavlović, Z., Brkić, Ž., Francija, E., Soldatović, I. A., Mitić, M., Radulović, J.,& Marić, N. P.. (2019). Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states. in Progress in Neuro-Psychopharmacology and Biological Psychiatry, 90, 288-299.
https://doi.org/10.1016/j.pnpbp.2018.12.011

Adžić M, Glavonić E, Nešić MJ, Milosavljević M, Mihaljević M, Petrović ZD, Pavlović Z, Brkić Ž, Francija E, Soldatović IA, Mitić M, Radulović J, Marić NP. Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states. in Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2019;90:288-299.
doi:10.1016/j.pnpbp.2018.12.011 .

Adžić, Miroslav, Glavonić, Emilija, Nešić, Milica J., Milosavljević, Minja, Mihaljević, Marina, Petrović, Zorica D., Pavlović, Zorana, Brkić, Željka, Francija, Ester, Soldatović, Ivan A., Mitić, Miloš, Radulović, Jelena, Marić, Nađa P., "Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states" in Progress in Neuro-Psychopharmacology and Biological Psychiatry, 90 (2019):288-299,
https://doi.org/10.1016/j.pnpbp.2018.12.011 . .

TY  - JOUR
AU  - Brkić, Željka
AU  - Milosavljević, Minja
AU  - Glavonić, Emilija
AU  - Adžić, Miroslav
PY  - 2019
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8359
AB  - Mitochondrial dysfunction can result from the interplay between elevated inflammatory markers and alterations in hypothalamic–pituitary–adrenal (HPA) axis, and can contribute to pathogenesis of major depression. Therefore, in this study we investigated whether the effects of lipopolysaccharide (LPS) on glucocorticoid receptor (GR) could be associated with alterations in mitochondrial apoptotic signaling in the prefrontal cortex of male and female Wistar rats with depressive-like behavior. To that end, we measured LPS-induced alterations in the extrinsic and intrinsic apoptotic pathways in mitochondria and cytosol of PFC of female and male rats, as well as the levels of cleaved cytosolic PARP-1. We also measured the mitochondrial levels of GR and its phosphoisoforms pGR232 and pGR246, as well as the mRNA levels of two GR-regulated mitochondrial genes, COX-1 and COX-3. We discovered that although seven-day LPS treatment evoked depressive-like behavior and induced apoptosis in the PFC of both sexes, it affected apoptotic cascades in both sexes differently. In females the treatment initiated both intrinsic and extrinsic apoptotic cascade, while in males only intrinsic cascade was engaged. Alterations in intrinsic apoptotic pathway were more associated with GR alterations in males, where LPS treatment decreased levels of mitochondrial GR and increased pGR232/pGR246 ratio. Alterations in mitochondrial GR could be associated with changes in expression of genes involved in oxidative metabolism in the PFC of this sex, and could, in combination with elevated levels of BCL-2 and decreased levels of BAX detected in this cell fraction, mitigate the detrimental effect of LPS on mitochondria in male PFC. © 2019
T2  - Brain Research Bulletin
T1  - Mitochondrial signaling in inflammation-induced depressive behavior in female and male rats: The role of glucocorticoid receptor
VL  - 150
SP  - 317
EP  - 327
DO  - 10.1016/j.brainresbull.2019.06.016
ER  - 

@article{
author = "Brkić, Željka and Milosavljević, Minja and Glavonić, Emilija and Adžić, Miroslav",
year = "2019",
abstract = "Mitochondrial dysfunction can result from the interplay between elevated inflammatory markers and alterations in hypothalamic–pituitary–adrenal (HPA) axis, and can contribute to pathogenesis of major depression. Therefore, in this study we investigated whether the effects of lipopolysaccharide (LPS) on glucocorticoid receptor (GR) could be associated with alterations in mitochondrial apoptotic signaling in the prefrontal cortex of male and female Wistar rats with depressive-like behavior. To that end, we measured LPS-induced alterations in the extrinsic and intrinsic apoptotic pathways in mitochondria and cytosol of PFC of female and male rats, as well as the levels of cleaved cytosolic PARP-1. We also measured the mitochondrial levels of GR and its phosphoisoforms pGR232 and pGR246, as well as the mRNA levels of two GR-regulated mitochondrial genes, COX-1 and COX-3. We discovered that although seven-day LPS treatment evoked depressive-like behavior and induced apoptosis in the PFC of both sexes, it affected apoptotic cascades in both sexes differently. In females the treatment initiated both intrinsic and extrinsic apoptotic cascade, while in males only intrinsic cascade was engaged. Alterations in intrinsic apoptotic pathway were more associated with GR alterations in males, where LPS treatment decreased levels of mitochondrial GR and increased pGR232/pGR246 ratio. Alterations in mitochondrial GR could be associated with changes in expression of genes involved in oxidative metabolism in the PFC of this sex, and could, in combination with elevated levels of BCL-2 and decreased levels of BAX detected in this cell fraction, mitigate the detrimental effect of LPS on mitochondria in male PFC. © 2019",
journal = "Brain Research Bulletin",
title = "Mitochondrial signaling in inflammation-induced depressive behavior in female and male rats: The role of glucocorticoid receptor",
volume = "150",
pages = "317-327",
doi = "10.1016/j.brainresbull.2019.06.016"
}

Brkić, Ž., Milosavljević, M., Glavonić, E.,& Adžić, M.. (2019). Mitochondrial signaling in inflammation-induced depressive behavior in female and male rats: The role of glucocorticoid receptor. in Brain Research Bulletin, 150, 317-327.
https://doi.org/10.1016/j.brainresbull.2019.06.016

Brkić Ž, Milosavljević M, Glavonić E, Adžić M. Mitochondrial signaling in inflammation-induced depressive behavior in female and male rats: The role of glucocorticoid receptor. in Brain Research Bulletin. 2019;150:317-327.
doi:10.1016/j.brainresbull.2019.06.016 .

Brkić, Željka, Milosavljević, Minja, Glavonić, Emilija, Adžić, Miroslav, "Mitochondrial signaling in inflammation-induced depressive behavior in female and male rats: The role of glucocorticoid receptor" in Brain Research Bulletin, 150 (2019):317-327,
https://doi.org/10.1016/j.brainresbull.2019.06.016 . .