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

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 was administered FLX (10 mg/kg/day) for 30 days (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.