N-3 polyunsaturated fatty acids and 17 beta-estradiol injection induce antidepressant-like effects through regulation of serotonergic neurotransmission in ovariectomized rats

Abstract

Previous studies have suggested that estrogen and n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have antidepressant-like effects. The purpose of the present study was to determine the interaction between n-3 PUFAs and estrogen, and their neurotrophic mechanism in rats after the forced swimming test (FST). Rats were fed a modified American Institute of Nutrition 93G diet with 0%, 1% or 2% EPA+DHA relative to the total energy intake during 12 weeks. At 8 weeks, rats were ovariectomized and injected with either 17 beta-estradiol-3-benzoate (E-2) or corn oil during the last 3 weeks. Both n-3 PUFA supplementation and E-2 injection increased climbing and decreased immobility during the FST. Serum serotonin concentration was also increased by both n-3 PUFA and E-2. N-3 PUFA and E-2 decreased hippocampal expressions of interleukin (IL)-6 and tumor necrosis factor-alpha, and increased cAMP response element binding protein (CREB), phosphorylated CREB and brain-derived neurotrophic factor (BDNF). N-3 PUFA supplementation decreased hippocampal expression of IL-1 beta only in rats injected with E-2. Both n-3 PUPA supplementation and E-2 injection increased estrogen receptor (ER)-alpha in the hippocampus, but ER-beta was increased only by E-2 injection. Additionally, there was a significant interaction between n-3 PUFA supplementation and E-2 injection on the hippocampal expression of pCREB, suggesting membrane-mediated interaction of n-3 PUFAs and E-2. In conclusion, both n-3 PUFA and E-2 had antidepressant-like effects by regulating serotonergic neurotransmission through BDNF and inflammatory cytokines.