Fluoxetine treatment induces dose dependent alterations in depression associated behavior and neural plasticity in female mice

Abstract

Antidepressant-induced increases in neurogenesis and neurotrophin mobilization in rodents and primates are proposed to be necessary for behavioral efficacy. The current study examines the relationship between the effects of fluoxetine treatment on behavior, cell proliferation and the neurotrophin BDNF in females. Female MRL/MpJ mice were treated acutely (5 and 10mg/kg) or chronically (2.5, 5 and 10mg/kg b.i.d.) with fluoxetine and tested in the tail suspension test (TST) and or novelty-induced hypophagia test (NIH), respectively. Mice treated chronically with fluoxetine received 4 (100mg/kg) injections of 5-bromo-2'-deoxyuridine (BrdU) on the last 4 days of treatment to measure DNA synthesis. The other half of the hippocampus and the frontal cortex was removed and examined for BDNF levels. Fluoxetine treatment decreased immobility in the TST and latency to eat in the NIH test, but only the highest dose of fluoxetine significantly altered behavior in both tests. Chronic treatment with 5 and 10mg/kg of fluoxetine significantly increased cell proliferation and BDNF levels in the hippocampus. Only chronic treatment with the highest of fluoxetine increased BDNF levels in the frontal cortex. Behavioral measures in the NIH test correlated with BDNF levels in the frontal cortex but not in the hippocampus or with cell proliferation in the hippocampus. These data suggest that females require high doses of fluoxetine for behavioral efficacy regardless of elevations of neurogenesis and BDNF mobilization in the hippocampus. Elevations in BDNF levels in the frontal cortex are related to the behavioral efficacy of fluoxetine.

Figure 1

Dose dependent effects of fluoxetine treatment on depression associated behaviors in female mice. A) Acute treatment with 10 mg/kg but not 5 mg/kg of fluoxetine reduced immobility in the tail suspension test. B) Chronic treatment with 10 mg/kg/day but not 5 mg/kg/day of fluoxetine decreased latency to eat in the novel cage during the NIH test. Bars represent mean values ± SEM. Asterisk (*) denotes significant differences, multiple asterisks indicate level of significance (* p < 0.05, ** p < 0.01).

Figure 2

Chronic treatment with fluoxetine produced dose dependent patterns of cell proliferation in the hippocampus of female mice. Treatment with 5 and 10 mg/kg/day increased cell proliferation when compared to saline treated animals and mice treated with 2. 5 mg/kg/day. Bars represent mean values ± SEM. Asterisk (*) denotes significant differences, multiple asterisks indicate level of significance (* p < 0.05, ** p < 0.01).

Figure 3

Chronic treatment with fluoxetine increased BDNF levels in the hippocampus and frontal cortex of female mice in a dose dependent manner. A) Treatment with 5 and 10 mg/kg/day increased BDNF levels in the hippocampus of female mice. B) Only the 10 mg/kg/day dose increased BDNF levels in the frontal cortex of female mice. Bars represent mean values ± SEM. Asterisk (*) denotes significant differences, multiple asterisks indicate level of significance (* p < 0.05, ** p < 0.01).

Figure 4

BDNF levels in the frontal cortex correlate with behavior in the NIH test. A) Female mice with higher levels of BDNF in the frontal cortex had a shorter latency to eat in the novel cage of the NIH test. B) Females with higher levels of BDNF in the frontal cortex ate more peanut butter chips in the novel cage of the NIH test.