Differential Rearing Alters Forced Swim Test Behavior, Fluoxetine Efficacy, and Post-Test Weight Gain in Male Rats

Abstract

Environmental factors play a key role in the etiology of depression. The rodent forced swim test (FST) is commonly used as a preclinical model of depression, with increases in escape-directed behavior reflecting antidepressant effects, and increases in immobility reflecting behavioral despair. Environmental enrichment leads to serotonergic alterations in rats, but it is unknown whether these alterations may influence the efficacy of common antidepressants. Male Sprague-Dawley rats were reared in enriched (EC), standard (SC), or isolated (IC) conditions. Following the rearing period, fluoxetine (10 or 20 mg/kg, i.p.) was administered 23.5 hrs, 5 hrs, and 1 hr before locomotor and FST measures. Following locomotor testing and FST exposure, rats were weighed to assess fluoxetine-, FST-, and environmental condition-induced moderations in weight gain. Results revealed an antidepressant effect of environmental enrichment and a depressant effect of isolation. Regardless of significant fluoxetine effects on locomotor activity, fluoxetine generally decreased swimming and increased immobility in all three environmental conditions, with IC-fluoxetine (10 mg/kg) rats and EC-fluoxetine (20 mg/kg) rats swimming less than vehicle counterparts. Subchronic 20 mg/kg fluoxetine also induced significant weight loss, and differential rearing appeared to moderate weight gain following FST stress. These results suggest that differential rearing has the ability to alter FST behaviors, fluoxetine efficacy, and post-stressor well-being. Moreover, 20 mg/kg fluoxetine, administered subchronically, may lead to atypical effects of those commonly observed in the FST, highlighting the importance and impact of both environmental condition and dosing regimen in common animal models of depression.

Fig 1. Experiment I Locomotor Activity following 10 mg/kg Fluoxetine.

Experiment I total locomotor distance (cm) traveled (±SEM) in EC and IC rats after subchronic fluoxetine (10 mg/kg, i.p.) or vehicle administrations 23.5 hrs, 5 hrs, and 1 hr before the locomotor test. Asterisk (*) indicates that EC rats exhibited less locomotor activity than did IC rats. Caret signs (^) indicate that fluoxetine rats exhibited less locomotor activity than vehicle rats (p < .05).

Fig 2. Experiment I Forced Swim Test Swimming.

Experiment I total mean counts (±SEM) of swimming behavior between EC and IC rats after subchronic fluoxetine (10 mg/kg, i.p.) or vehicle administrations 23.5 hrs, 5 hrs, and 1 hr before the FST. Asterisk (*) indicates IC rats receiving vehicle exhibited significantly more swimming than IC rats receiving fluoxetine injections (p < .05).

Fig 3. Experiment II Locomotor Activity Following 20 mg/kg Fluoxetine.

Experiment II total locomotor distance (cm) traveled (±SEM) in EC, SC, and IC rats after subchronic fluoxetine (20 mg/kg, i.p.) or vehicle administrations 23.5 hrs, 5 hrs, and 1 hr before the locomotor test. Asterisks (*) indicate significant reductions in locomotor activity in fluoxetine-treated rats compared to vehicle controls for all three environmental conditions. Caret sign (^) indicates significant reductions in locomotor activity in EC-vehicle rats compared to both SC- and IC-vehicle rats (p < .05).

Fig 4. Experiment II Pretest Swimming, Climbing, and Immobility.

Experiment II total mean counts (±SEM) of (A) climbing, (B) swimming, and (C) immobility behavior between EC, SC, and IC rats during the first five minutes of the forced swim pretest. (A) Asterisk (*) indicates EC rats exhibited significantly more climbing than both SC and IC rats during the first five minutes of the pretest. (B) Asterisk (*) indicates IC rats exhibited significantly less swimming than SC rats during the first five minutes of the pretest (p < .05).

Fig 5. Experiment II Forced Swim Test Swimming Behavior Experiment II total mean counts (±SEM) of swimming behavior between EC, SC, and IC rats after subchronic fluoxetine (20 mg/kg, i.p.) or vehicle administrations before the FST.

Asterisk (*) indicates EC rats receiving fluoxetine exhibited significantly less swimming than EC rats receiving vehicle injections (p < .05).

Fig 6. Experiment III Pretest Climbing and Swimming.

Experiment III total mean counts (±SEM) of (A) climbing and (B) swimming behavior between EC, SC, and IC rats during the first five minutes of the forced swim pretest. (A) Asterisk (*) indicates EC rats exhibited significantly more climbing than SC rats during the first five minutes of the pretest. (B) Asterisk (*) indicates IC rats exhibited significantly less swimming than SC rats during the first five minutes of the pretest (p < .05).

Fig 7. Experiment III Forced Swim Test Climbing, Swimming, and Immobility.

Experiment III total mean counts (±SEM) of (A) climbing, (B) swimming, and (C) immobility behavior between EC, SC, and IC rats after subchronic fluoxetine (20 mg/kg, i.p.) or vehicle administrations before the FST. (A) Asterisk (*) indicates that EC rats exhibited more climbing behavior than SC rats, irrespective of drug treatment. (B) Asterisks (*) indicate that fluoxetine rats exhibited less swimming behavior than vehicle control rats. (C) Asterisks (*) indicate that fluoxetine rats exhibited significantly more immobility than rats administered vehicle control injections (p < .05).

Fig 8. Percent Change in Body Weight.

Percent change in body weight from baseline after FST and subchronic fluoxetine (20 mg/kg, i.p.) in EC, IC, and SC rats in cohort I. Day 1 reflects body weights before fluoxetine and FST exposure. The significant interaction between drug and environmental condition on rats' percent change in weight depends on the time that has passed since fluoxetine or vehicle administration (p < .05).

Fig 9. Percent Change in Body Weight.

Percent change in body weight from baseline after FST and subchronic fluoxetine (20 mg/kg, i.p.) in EC, IC, and SC rats in cohort II. Day 1 reflects body weights before fluoxetine and FST exposure. The significant interaction between drug and environmental condition on rats' percent change in weight depends on the time that has passed since fluoxetine or vehicle administration (p < .05).