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Objective@#Atomoxetine and fluoxetine are psychopharmacologic agents associated with loss of appetite and weight. Adenosine monophosphate-activated protein kinase (AMPK) is the cellular energy sensor that regulate metabolism and energy, being activated by fasting and inhibited by feeding in the hypothalamus. @*Methods@#Human brain cell lines (SH-SY5Y and U-87 MG cells) were used to study the outcome of atomoxetine and fluoxetine treatment in the activity of AMPK-acetyl-CoA carboxylase (ACC)- carnitine palmitoyl transferase 1 (CPT1) pathway and upstream regulation by calcium/calmodulin-dependent kinase kinase β (CaMKKβ) using immunoblotting and CPT1 enzymatic activity measures. @*Results@#Phosphorylation of AMPK and ACC increased significantly after atomoxetine and fluoxetine treatment in the first 30–60 minutes of treatment in the two cell lines. Activation of AMPK and inhibition of ACC was associated with an increase by 5-fold of mitochondrial CPT1 activity. Although the neuronal isoform CPT1C could be detected by immunoblotting, activity was not changed by the drug treatments. In addition, the increase in phospho-AMPK and phospho-ACC expression induced by atomoxetine was abolished by treatment with STO-609, a CaMKKβ inhibitor, indicating that AMPK-ACC-CPT1 pathway is activated through CaMKKβ phosphorylation. @*Conclusion@#These findings indicate that at the cellular level atomoxetine and fluoxetine treatments may activate AMPK-ACC-CPT1 pathways through CaMKKβ in human SH-SY5Y and U-87 MG cells.
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Objectives@#ZZKetamine has been reported to have antidepressant effects or psychotomimetic effects. The aim of this study was to investigatethe behavioral effects of ketamine treatment at various sub-anesthetic doses in adolescent and adult naïve mice. @*Methods@#ZZIn each experiment for adolescent and adult mice, a total of 60 male Institute of Cancer Research mice were randomly dividedinto 6 groups, which were intraperitoneally treated with physiological saline, 10, 20, 30, 40, and 50 mg/kg ketamine for consecutive3 days. At 1 day after last injection, the locomotor and depressive-like behaviors were evaluated in mice, using open field test (OFT)and forced swim test (FST), respectively. @*Results@#ZZIn case of adolescent mice, ketamine dose was negatively correlated with total distance traveled in the OFT (Spearman’srho = -0.27, p = 0.039). In case of adult mice, we found significant positive correlation between ketamine dose and duration of immobilityin the FST (Spearman’s rho = 0.45, p < 0.001). Immobility time in the 50 mg/kg ketamine-treated mice was significantly higher comparedto the saline-treated mice (Dunnett’s post-hoc test, p = 0.012). @*Conclusions@#ZZWe found that the repeated treatment with ketamine could decrease the locomotor or prolong the duration of immobilityin mice as the dose of ketamine increased. Our findings suggest that sub-anesthetic doses of ketamine might induce schizophrenia-like negative symptoms but not antidepressant effects in naïve laboratory animals.
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Objectives@#ZZKetamine has been reported to have antidepressant effects or psychotomimetic effects. The aim of this study was to investigatethe behavioral effects of ketamine treatment at various sub-anesthetic doses in adolescent and adult naïve mice. @*Methods@#ZZIn each experiment for adolescent and adult mice, a total of 60 male Institute of Cancer Research mice were randomly dividedinto 6 groups, which were intraperitoneally treated with physiological saline, 10, 20, 30, 40, and 50 mg/kg ketamine for consecutive3 days. At 1 day after last injection, the locomotor and depressive-like behaviors were evaluated in mice, using open field test (OFT)and forced swim test (FST), respectively. @*Results@#ZZIn case of adolescent mice, ketamine dose was negatively correlated with total distance traveled in the OFT (Spearman’srho = -0.27, p = 0.039). In case of adult mice, we found significant positive correlation between ketamine dose and duration of immobilityin the FST (Spearman’s rho = 0.45, p < 0.001). Immobility time in the 50 mg/kg ketamine-treated mice was significantly higher comparedto the saline-treated mice (Dunnett’s post-hoc test, p = 0.012). @*Conclusions@#ZZWe found that the repeated treatment with ketamine could decrease the locomotor or prolong the duration of immobilityin mice as the dose of ketamine increased. Our findings suggest that sub-anesthetic doses of ketamine might induce schizophrenia-like negative symptoms but not antidepressant effects in naïve laboratory animals.
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OBJECTIVE: Synaptic vesicle mobilization and neurite outgrowth regulation molecules were examined in modulation of effects of methylphenidate (MPH) in Spontaneous Hypertensive Rats (SHRs), a model for attention-deficit hyperactivity disorder (ADHD). METHODS: We compared the changes in the protein expression level of Cyclin dependent kinase 5 (Cdk5) and molecular substrates of Cdk5; tropomyosin receptor kinase B (TrkB), syntaxin 1A (STX1A) and synaptosomal-associated protein 25 (SNAP25). Comparisons were made in prefrontal cortex of vehicle (distilled water i.p. for 7 days)-treated SHRs, vehicle-treated Wistar Kyoto Rats (WKYs) and MPH (2 mg/kg i.p. for 7 days) treated SHRs. RESULTS: The Cdk5 level of vehicle-treated SHRs was significantly decreased compared to the Cdk5 level of vehicle-treated WKY rats, but was restored to the expression level of vehicle-treated WKYs in MPH-treated SHR. The ratio of p25/p35 was significantly decreased in MPH-treated SHR compared to vehicle-treated SHR. Moreover, TrkB, STX1A and SNAP25 of vehicle-treated SHRs were significantly decreased compared to vehicle-treated WKY rats, but were restored to the expression level of vehicle-treated WKYs in MPH-treated SHR. CONCLUSION: The results show that Cdk5, TrkB, STX1A, and SNAP25 were involved in the modulation of MPH effects in prefrontal cortex of SHRs and play important role in treatment of ADHD.