| In Vitro | In vitro activity: Fluoxetine blocks the downregulation of cell proliferation resulting from inescapable shock (IS) of hippocampal cell. Fluoxetine increases the number of newborn cells in the dentate gyrus of the hippocampus of adult rat. Fluoxetine also increases the number of proliferating cells in the prelimbic cortex. Fluoxetine accelerates the maturation of immature neurons. Fluoxetine enhances neurogenesis-dependent long-term potentiation (LTP) in the dentate gyrus. Fluoxetine, but not citalopram, fluvoxamine, paroxetine and sertraline, increases norepinephrine and dopamine extracellular levels in prefrontal cortex. Fluoxetine produces robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration.
Cell Assay: In Xenopusoocytes expressing either cloned 5HT2C receptors or 5HT receptors, micromolar concentrations of fluoxetine (Prozac) inhibited the membrane currents elicited by serotonin (5-hydroxytryptamine; 5HT). For responses elicited by 1 μM 5-HT, the IC50 of fluoxetine was about 20 μM. Fluoxetine also inhibited the binding of [3H]5HT to 5HT2C receptors expressed in HeLa cells and the binding of [3H]5HT to 5HT receptors in rat cortex membranes, with Ki of ≈65–97 nM and ≈ 56 μM, respectively. Administration of fluoxetine blocked the downregulation of cell proliferation of hippocampal cells resulting from inescapable shock (IS), which resulted in a state of behavioral despair. Fluoxetine increased the number of newborn cells in the dentate gyrus of the hippocampus of adult rat. Fluoxetine also increased the number of proliferating cells in the prelimbic cortex. Fluoxetine accelerated the maturation of immature neurons. Fluoxetine enhanced neurogenesis-dependent long-term potentiation (LTP) in the dentate gyrus. Fluoxetine, but not other selective serotonin uptake inhibitors such as citalopram, fluvoxamine, paroxetine and sertraline, increased norepinephrine and dopamine extracellular levels in prefrontal cortex. Fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. |
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| Formulation & Dosage | Male Sprague-Dawley rats weighing 250-300 g are housed under a 12-hour light/12-hour dark cycle (lights on at 7:00 am, lights off at 7:00 pm) and at constant temperature (25°C) and humidity and allowed free access to food and water. For chronic drug treatments, rats are administered fluoxetine (5 mg/kg/day) or saline by intraperitoneal (IP) injection once daily and olanzapine or vehicle in the drinking water for 21 days (vehicle-treated control, fluoxetine, and olanzapine alone) plus the combination of fluoxetine and olanzapine. For combination treatment, olanzapine is chosen because fluoxetine is known to interfere with the metabolism of olanzapine and raise the blood levels by up to 4-6 times. Olanzapine is dissolved in hydrochloric acid (HCl), then adjusted back to pH 6 with 1 N sodium hydroxide to make the stock solution of 3 mg/mL concentration. The same amount of vehicle solution is added to the water for the control animals. Fluid intake is measured three times per week, and drinking bottles are replenwashed with fresh drug solution. There are no differences in fluid intake among the treatment groups. For subchronic treatment, drugs are administered exactly the same way but for a total period of 7 days. |
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