Mirković, Kristina

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orcid::0009-0000-2208-2252
  • Mirković, Kristina (2)
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Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats

Aranđelović, Jovana; Kojić, Jana; Mirković, Kristina; Jančić, Ivan; Todorović, Lidija; Savić, Miroslav

(European College of Neuropsychopharmacology (ECNP), 2023)

TY  - CONF
AU  - Aranđelović, Jovana
AU  - Kojić, Jana
AU  - Mirković, Kristina
AU  - Jančić, Ivan
AU  - Todorović, Lidija
AU  - Savić, Miroslav
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5520
AB  - Introduction: Impulsivity is an umbrella term that encompasses many subdomains, most of which rely on the decision-making processes. It is reported that in the process of healthy aging, the two dimensions of impulse control, cognition and motivation, are preserved or even improved. On the other hand, the attentive efficiency seems to decrease with age. Therefore, we aimed to investigate the effects of healthy aging on impulsivity in rats and the influence of food deprivation on impulsivity in aged rats as a strategy to enhance motivation. Additionally, we wanted to assess the gene expression for the alpha5 GABAA receptor subunit during aging, which plays a role in cognitive processes. Methodology: The variable-delay-to-signal (VDS) paradigm adapted to a touchscreen environment was used to assess impulsivity and attention in Sprague-Dawley rats at 2, 3, 5, 8, and 14 months of age. After one week of training, animals were tested at different ages in 3-stage testing protocol. Additionally, prior to testing, animals were fed a restricted diet (16 g/animal). The first stage included 20 trials with inter-trial interval of 6s (ITI6si) that reflected motor impulsivity. The second stage, with 60 randomly distributed trials of ITI9s or 15s, was related to delay intolerance, while the final stage (ITI6sf), similar to the first, was related to reflection impulsivity. The strict 3-day restriction diet (24h food deprivation followed by 10g/day/animal and 8g/day/animal) was applied to 14-month-old animals before testing. Gabra5 expression in the hippocampus was determined by qPCR. Results were analyzed by one-way ANOVA with or without repeated measures, followed by Sidak post-hoc test for impulsivity and attention parameters and by t-test for PCR parameters. Results: Animals aged 8 and 14 months had reduced motor impulsivity (p<0.01 for both groups) and delay intolerance (p<0.05 for both groups) and higher number of omissions (p<0.05 for both groups) compared to animals aged 2, 3 and 5 months of age. In addition, half of the animals were unable to successfully complete a task after 14 months. After rigorous food restriction in 14-month-old animals, the level of impulsivity (ITI9s and ITI15s) and attention (number of omissions) returned to the control level (2 and 3 months of age) compared to the performance of 14-month-old animals prior to rigorous food restriction (p<0.05). Further, the peak of reflection impulsivity (ITI6sf) was reached at 5 months compared to all other groups (p<0.01). No changes in Gabra5 expression in hippocampus were detected in 14-month-old compared to 3-month-old animals. Conclusion: From 8 months of age onwards, rats showed reduced impulsivity in the VDS stages where motor impulsivity and delay intolerance were tested, followed by attention deficits. After strict food restriction in 14-month-old animals, delay intolerance and attention were restored, suggesting the prominent role of motivation in controlling these processes, independently of Gabra5 expression levels in the hippocampus. Since the VDS paradigm aims to assess reward-related impulsivity based on cognition and motivation, it is suspected that results related to impaired cognition in older animals in other cognitive tests should be interpreted with caution, and with additional observation of motivation.
PB  - European College of Neuropsychopharmacology (ECNP)
C3  - 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain
T1  - Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5520
ER  - 
@conference{
author = "Aranđelović, Jovana and Kojić, Jana and Mirković, Kristina and Jančić, Ivan and Todorović, Lidija and Savić, Miroslav",
year = "2023",
abstract = "Introduction: Impulsivity is an umbrella term that encompasses many subdomains, most of which rely on the decision-making processes. It is reported that in the process of healthy aging, the two dimensions of impulse control, cognition and motivation, are preserved or even improved. On the other hand, the attentive efficiency seems to decrease with age. Therefore, we aimed to investigate the effects of healthy aging on impulsivity in rats and the influence of food deprivation on impulsivity in aged rats as a strategy to enhance motivation. Additionally, we wanted to assess the gene expression for the alpha5 GABAA receptor subunit during aging, which plays a role in cognitive processes. Methodology: The variable-delay-to-signal (VDS) paradigm adapted to a touchscreen environment was used to assess impulsivity and attention in Sprague-Dawley rats at 2, 3, 5, 8, and 14 months of age. After one week of training, animals were tested at different ages in 3-stage testing protocol. Additionally, prior to testing, animals were fed a restricted diet (16 g/animal). The first stage included 20 trials with inter-trial interval of 6s (ITI6si) that reflected motor impulsivity. The second stage, with 60 randomly distributed trials of ITI9s or 15s, was related to delay intolerance, while the final stage (ITI6sf), similar to the first, was related to reflection impulsivity. The strict 3-day restriction diet (24h food deprivation followed by 10g/day/animal and 8g/day/animal) was applied to 14-month-old animals before testing. Gabra5 expression in the hippocampus was determined by qPCR. Results were analyzed by one-way ANOVA with or without repeated measures, followed by Sidak post-hoc test for impulsivity and attention parameters and by t-test for PCR parameters. Results: Animals aged 8 and 14 months had reduced motor impulsivity (p<0.01 for both groups) and delay intolerance (p<0.05 for both groups) and higher number of omissions (p<0.05 for both groups) compared to animals aged 2, 3 and 5 months of age. In addition, half of the animals were unable to successfully complete a task after 14 months. After rigorous food restriction in 14-month-old animals, the level of impulsivity (ITI9s and ITI15s) and attention (number of omissions) returned to the control level (2 and 3 months of age) compared to the performance of 14-month-old animals prior to rigorous food restriction (p<0.05). Further, the peak of reflection impulsivity (ITI6sf) was reached at 5 months compared to all other groups (p<0.01). No changes in Gabra5 expression in hippocampus were detected in 14-month-old compared to 3-month-old animals. Conclusion: From 8 months of age onwards, rats showed reduced impulsivity in the VDS stages where motor impulsivity and delay intolerance were tested, followed by attention deficits. After strict food restriction in 14-month-old animals, delay intolerance and attention were restored, suggesting the prominent role of motivation in controlling these processes, independently of Gabra5 expression levels in the hippocampus. Since the VDS paradigm aims to assess reward-related impulsivity based on cognition and motivation, it is suspected that results related to impaired cognition in older animals in other cognitive tests should be interpreted with caution, and with additional observation of motivation.",
publisher = "European College of Neuropsychopharmacology (ECNP)",
journal = "36th ECPN congress, 7th -10th October 2023, Barcelona, Spain",
title = "Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5520"
}
Aranđelović, J., Kojić, J., Mirković, K., Jančić, I., Todorović, L.,& Savić, M.. (2023). Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats. in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain
European College of Neuropsychopharmacology (ECNP)..
https://hdl.handle.net/21.15107/rcub_farfar_5520
Aranđelović J, Kojić J, Mirković K, Jančić I, Todorović L, Savić M. Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats. in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain. 2023;.
https://hdl.handle.net/21.15107/rcub_farfar_5520 .
Aranđelović, Jovana, Kojić, Jana, Mirković, Kristina, Jančić, Ivan, Todorović, Lidija, Savić, Miroslav, "Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats" in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain (2023),
https://hdl.handle.net/21.15107/rcub_farfar_5520 .

Deciphering ciprofloxacin-induced neurotoxicity: behavioral and molecular profiling of ciprofloxacin treatment in rats

Mirković, Kristina; Aranđelović, Jovana; Kojić, Jana; Stevanović, Vladimir; Batinić, Bojan; Todorović, Vanja; Đoković, Jelena; Santrač, Anja; Major, Tamara; Savić, Miroslav

(European College of Neuropsychopharmacology (ECNP), 2023)

TY  - CONF
AU  - Mirković, Kristina
AU  - Aranđelović, Jovana
AU  - Kojić, Jana
AU  - Stevanović, Vladimir
AU  - Batinić, Bojan
AU  - Todorović, Vanja
AU  - Đoković, Jelena
AU  - Santrač, Anja
AU  - Major, Tamara
AU  - Savić, Miroslav
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5521
AB  - Introduction: Ciprofloxacin is a fluoroquinolone antibiotic commonly used to treat various bacterial infections, with a potential to induce adverse mood effects in patients. Since the molecular mechanism of ciprofloxacin-induced neurotoxicity is poorly understood, we aimed to identify behavioral changes and corresponding neurotransmitter pattern after its prolonged administration in rats. We screened for untoward effects of ciprofloxacin on locomotor activity, despair, anhedonia, object recognition memory, and anxiety, as behavioral domains affected in various psychiatric diseases. Methodology: Three-month old male Sprague-Dawley rats were orally gavaged with ciprofloxacin (20 or 100 mg/kg) or solvent (0.5% methyl cellulose solution) each day for 4 weeks (n=80). One group of animals (n=40) passed the open field (OF), novel object recognition test (NORT), and forced swimming test (FST). Another group (n=40) underwent elevated plus maze (EPM) and sucrose preference test (SPT). After the completion of behavioral battery, the prefrontal cortex and cerebrospinal fluid (CSF) were collected. The neurotransmitters and metabolites of the kynurenine pathway were determined in the prefrontal cortex (PFC) through HPLC-MS/MS. Additionally, levels of interleukin-2 (IL-2) in CSF were quantified with Luminex. Behavioral and molecular parameters were analyzed by one-way ANOVA followed by Dunnett post hoc test in GraphPad Prism 9. Results: In FST, the treatment with high dose of ciprofloxacin decreased the swim time compared to control, which could be related to induction of despair-like behavior (p<0.05). The ciprofloxacin treatment did not affect object memory in NORT. In OF, the distance travelled and the number of rotations were not changed after treatment with ciprofloxacin compared to the control group. Further, animals treated with ciprofloxacin did not show changes in parameters in EPM and SPT. The acetylcholine levels in PFC were increased after ciprofloxacin treatment (p<0.05) in comparison with controls, which could be associated with depressed mood states. In line with that, high dose of ciprofloxacin treatment showed the tendency to decrease and increase levels of GABA and dopamine, respectively, but without reaching the statistical significance (p=0.07 and p=0.06). No changes in kynurenine pathway were observed after the treatment. The IL-2 concentration in CSF was increased after prolonged administration of low dose of ciprofloxacin treatment compared to the control levels (p<0.05), which could imply immunological stimulation of T lymphocytes and potential neuroinflammation. Conclusion: The despair behavior after treatment with high dose of ciprofloxacin was accompanied by increased levels of acetylcholine in PFC. Furthermore, the high dose of ciprofloxacin treatment showed tendency to decrease GABA levels, and increase dopamine levels in PFC, which could be connected to psychiatric adverse effects. Nonetheless, further studies are essential to confirm these neurotransmitter changes. On the other hand, the low dose of ciprofloxacin treatment elicited the increase of IL-2, which could be a marker of neuroinflammation-related neurotoxicity. In the future, efforts should be made to examine the role of IL-2 in the interaction of the immune system and the central nervous system, as its potential significance as a biomarker.
PB  - European College of Neuropsychopharmacology (ECNP)
C3  - 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain
T1  - Deciphering ciprofloxacin-induced neurotoxicity: behavioral and molecular profiling of ciprofloxacin treatment in rats
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5521
ER  - 
@conference{
author = "Mirković, Kristina and Aranđelović, Jovana and Kojić, Jana and Stevanović, Vladimir and Batinić, Bojan and Todorović, Vanja and Đoković, Jelena and Santrač, Anja and Major, Tamara and Savić, Miroslav",
year = "2023",
abstract = "Introduction: Ciprofloxacin is a fluoroquinolone antibiotic commonly used to treat various bacterial infections, with a potential to induce adverse mood effects in patients. Since the molecular mechanism of ciprofloxacin-induced neurotoxicity is poorly understood, we aimed to identify behavioral changes and corresponding neurotransmitter pattern after its prolonged administration in rats. We screened for untoward effects of ciprofloxacin on locomotor activity, despair, anhedonia, object recognition memory, and anxiety, as behavioral domains affected in various psychiatric diseases. Methodology: Three-month old male Sprague-Dawley rats were orally gavaged with ciprofloxacin (20 or 100 mg/kg) or solvent (0.5% methyl cellulose solution) each day for 4 weeks (n=80). One group of animals (n=40) passed the open field (OF), novel object recognition test (NORT), and forced swimming test (FST). Another group (n=40) underwent elevated plus maze (EPM) and sucrose preference test (SPT). After the completion of behavioral battery, the prefrontal cortex and cerebrospinal fluid (CSF) were collected. The neurotransmitters and metabolites of the kynurenine pathway were determined in the prefrontal cortex (PFC) through HPLC-MS/MS. Additionally, levels of interleukin-2 (IL-2) in CSF were quantified with Luminex. Behavioral and molecular parameters were analyzed by one-way ANOVA followed by Dunnett post hoc test in GraphPad Prism 9. Results: In FST, the treatment with high dose of ciprofloxacin decreased the swim time compared to control, which could be related to induction of despair-like behavior (p<0.05). The ciprofloxacin treatment did not affect object memory in NORT. In OF, the distance travelled and the number of rotations were not changed after treatment with ciprofloxacin compared to the control group. Further, animals treated with ciprofloxacin did not show changes in parameters in EPM and SPT. The acetylcholine levels in PFC were increased after ciprofloxacin treatment (p<0.05) in comparison with controls, which could be associated with depressed mood states. In line with that, high dose of ciprofloxacin treatment showed the tendency to decrease and increase levels of GABA and dopamine, respectively, but without reaching the statistical significance (p=0.07 and p=0.06). No changes in kynurenine pathway were observed after the treatment. The IL-2 concentration in CSF was increased after prolonged administration of low dose of ciprofloxacin treatment compared to the control levels (p<0.05), which could imply immunological stimulation of T lymphocytes and potential neuroinflammation. Conclusion: The despair behavior after treatment with high dose of ciprofloxacin was accompanied by increased levels of acetylcholine in PFC. Furthermore, the high dose of ciprofloxacin treatment showed tendency to decrease GABA levels, and increase dopamine levels in PFC, which could be connected to psychiatric adverse effects. Nonetheless, further studies are essential to confirm these neurotransmitter changes. On the other hand, the low dose of ciprofloxacin treatment elicited the increase of IL-2, which could be a marker of neuroinflammation-related neurotoxicity. In the future, efforts should be made to examine the role of IL-2 in the interaction of the immune system and the central nervous system, as its potential significance as a biomarker.",
publisher = "European College of Neuropsychopharmacology (ECNP)",
journal = "36th ECPN congress, 7th -10th October 2023, Barcelona, Spain",
title = "Deciphering ciprofloxacin-induced neurotoxicity: behavioral and molecular profiling of ciprofloxacin treatment in rats",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5521"
}
Mirković, K., Aranđelović, J., Kojić, J., Stevanović, V., Batinić, B., Todorović, V., Đoković, J., Santrač, A., Major, T.,& Savić, M.. (2023). Deciphering ciprofloxacin-induced neurotoxicity: behavioral and molecular profiling of ciprofloxacin treatment in rats. in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain
European College of Neuropsychopharmacology (ECNP)..
https://hdl.handle.net/21.15107/rcub_farfar_5521
Mirković K, Aranđelović J, Kojić J, Stevanović V, Batinić B, Todorović V, Đoković J, Santrač A, Major T, Savić M. Deciphering ciprofloxacin-induced neurotoxicity: behavioral and molecular profiling of ciprofloxacin treatment in rats. in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain. 2023;.
https://hdl.handle.net/21.15107/rcub_farfar_5521 .
Mirković, Kristina, Aranđelović, Jovana, Kojić, Jana, Stevanović, Vladimir, Batinić, Bojan, Todorović, Vanja, Đoković, Jelena, Santrač, Anja, Major, Tamara, Savić, Miroslav, "Deciphering ciprofloxacin-induced neurotoxicity: behavioral and molecular profiling of ciprofloxacin treatment in rats" in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain (2023),
https://hdl.handle.net/21.15107/rcub_farfar_5521 .