Fluoxetine dose and administration method differentially affect hippocampal plasticity in adult female rats

Abstract

Selective serotonin reuptake inhibitor medications are one of the most common treatments for mood disorders. In humans, these medications are taken orally, usually once per day. Unfortunately, administration of antidepressant medications in rodent models is often through injection, oral gavage, or minipump implant, all relatively stressful procedures. The aim of the present study was to investigate how administration of the commonly used SSRI, fluoxetine, via a wafer cookie, compares to fluoxetine administration using an osmotic minipump, with regards to serum drug levels and hippocampal plasticity. For this experiment, adult female Sprague-Dawley rats were divided over the two administration methods: (1) cookie and (2) osmotic minipump and three fluoxetine treatment doses: 0, 5, or 10 mg/kg/day. Results show that a fluoxetine dose of 5 mg/kg/day, but not 10 mg/kg/day, results in comparable serum levels of fluoxetine and its active metabolite norfluoxetine between the two administration methods. Furthermore, minipump administration of fluoxetine resulted in higher levels of cell proliferation in the granule cell layer (GCL) at a 5 mg dose compared to a 10 mg dose. Synaptophysin expression in the GCL, but not CA3, was significantly lower after fluoxetine treatment, regardless of administration method. These data suggest that the administration method and dose of fluoxetine can differentially affect hippocampal plasticity in the adult female rat.

Figure 1

(a) Photomicrograph representing Ki67 immunoreactive cells in the dentate gyrus. (b) Drawing of hippocampal areas selected for quantification of synaptophysin expression and (c) a photomicrograph representing synaptophysin immunohistochemistry in the hippocampus (40x). Scale bar = 10 μm.

Figure 2

Mean (±SEM) serum levels of fluoxetine (a, c) and norfluoxetine (b, d) (ng/mL). (a, b) There were significantly higher serum levels of fluoxetine/norfluoxetine in the animals receiving 10 mg/kg/day of fluoxetine via minipump. Serum levels were significantly lower in the morning and were significantly higher in the minipump group (0.000001 < P < 0.015). (c, d) At sacrifice, serum from trunk blood revealed significantly higher levels of fluoxetine/norfluoxetine in the animals receiving 10 mg/kg/day of fluoxetine via minipump (0.00001 < P < 0.03). (n = 6/group). ∗∗ denotes 10 mg significantly different from all other groups.

Figure 3

Mean (±SEM) total number of Ki67-ir cells in the GCL/SGZ. Minipump animals receiving the 5 mg/kg/day dose of fluoxetine had significantly more Ki67-ir cells in the GCL compared to minipump animals receiving the 10 mg/kg/day dose, when looking at overall change from baseline (control) (P = 0.013). (n = 5-6/group). Dashed line indicates baseline.

Figure 4

Mean (±SEM) synaptophysin expression in the GCL/SGZ of the hippocampus. Synaptophysin density was significantly greater in vehicle-treated animals, regardless of administration method (0.000001 < P < 0.03). (n = 6/group). ∗ denotes 0 mg significantly different from 5 mg and 10 mg.