Omega-3 fatty acid deficiency does not alter the effects of chronic fluoxetine treatment on central serotonin turnover or behavior in the forced swim test in female rats

Abstract

While translational evidence suggests that long-chain omega-3 fatty acid status is positively associated with the efficacy of selective serotonin reuptake inhibitor drugs, the neurochemical mechanisms mediating this interaction are not known. Here we investigated the effects of dietary omega-3 (n-3) fatty acid insufficiency on the neurochemical and behavioral effects of chronic fluoxetine (FLX) treatment. Female rats were fed diets with (CON, n=56) or without (DEF, n=40) the n-3 fatty acids during peri-adolescent development (P21-P90), and one half of each group were administered FLX (10 mg/kg/d) for 30 d (P60-P90) prior to testing. In adulthood (P90), regional brain serotonin (5-HT) and 5-hydroxyindoleacetic (5-HIAA) concentrations, presynaptic markers of 5-HT neurotransmission, behavioral responses in the forced swim test (FST), and plasma FLX and norfluoxetine (NFLX) concentrations were investigated. Peri-adolescent n-3 insufficiency led to significant reductions in cortical docosahexaenoic acid (DHA, 22:6n-3) composition in DEF (−25%, p≤0.0001) and DEF+FLX (−28%, p≤0.0001) rats. Untreated DEF rats exhibited significantly lower regional 5-HIAA/5-HT ratios compared with untreated CON rats, but exhibited similar behavioral responses in the FST. In both CON and DEF rats, chronic FLX treatment similarly and significantly decreased 5-HIAA concentrations and the 5-HIAA/5-HT ratio in the hypothalamus, hippocampus, and nucleus accumbens, brainstem tryptophan hydroxylase-2 mRNA expression, and immobility in the FST. While the FLX-induced reduction in 5-HIAA concentrations in the prefrontal cortex was significantly blunted in DEF rats, the reduction in the 5-HIAA/5-HT ratio was similar to CON rats. Although plasma FLX and NFLX levels were not significantly different in DEF and CON rats, the NFLX/FLX ratio was significantly lower in DEF+FLX rats. These preclinical data demonstrate that n-3 fatty acid deficiency does not significantly reduce the effects of chronic FLX treatment on central 5-HT turnover or behavior in the FST in female rats.

Gestational stress and fluoxetine treatment differentially affect plasticity, methylation and serotonin levels in the PFC and hippocampus of rat dams

“…In the hippocampus of rat dams we found that fluoxetine, regardless of gestational stress exposure, decreased serotonergic functioning. This work is in line with previous work showing that chronic fluoxetine administration to female rats reduces hippocampal 5-HIAA/5-HT ratios (McNamara et al, 2013) and that sub-chronic exposure to the SSRI sertraline decreases 5-HIAA/5-HT levels in the hippocampus of male rats, regardless of stress exposure (Mikail et al, 2012). These findings highlight that serotonergic metabolism of the hippocampus is particularly sensitive to SSRI treatment during adulthood.…”

Antidepressants but not antipsychotics have antiepileptogenic effects with limited effects on comorbid depressive‐like behaviour in theWAG/Rij rat model of absence epilepsy

“…Quetiapine's half‐life (about 7 h) is identical between rats and humans (Nemeroff et al ., ), and the dose used (10 mg·kg −1 day −1 ) is very similar to the one used in clinical practice (about 600–800 mg day −1 ) (Cerullo and Strakowski, ). Fluoxetine is generally used at 20–60 mg day −1 in patients; in a pharmacokinetic study, a daily dose of 20 mg achieved a mean plasma concentration of about 80 ng·mL −1 (Norman et al ., ); this is in agreement with the mean plasma concentration found in rats after 3 days of treatment with fluoxetine at a dose of 10 mg·kg −1 (McNamara et al ., ). Duloxetine is used in patients at range doses of 30–120 mg day −1 and a pharmacokinetic study showed that, in patients, plasma levels ranged between 5 and 135 ng·mL −1 (mean 53.56 ng·mL −1 ) and plasma levels were significantly correlated with efficacy, but also with signs of anxiety and irritability at the highest concentrations (Volonteri et al ., ).…”

Dietary DHA during development affects depression-like behaviors and biomarkers that emerge after puberty in adolescent rats

“…On the other hand, McNamara et al ( 87 ) reported that feeding omega-3 PUFA-suffi cient diets from weaning to adulthood (P21-P90) in female rats had no effect on FST behavior compared with omega-3 PUFA-insuffi cient controls. This suggests that there may be a sex difference in the effect of postweaning omega-3 PUFA supplementation on depressive-like behaviors.…”