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Abstract
The beneficial effects of omega (ω)-3 polyunsaturated fatty acid (PUFA) supplementation on major depressive disorder have been actively studied, but the underlying mechanism remains unknown. The present study examined the involvement of the nucleus accumbens (NAc) dopaminergic systems in behavioral changes in mice fed a diet high in ω-3 PUFAs. Mice fed a diet containing about double the amount of ω-3 PUFAs (krill oil (KO) diet) exerted shorter immobility times in the forced swim test (FST) than mice fed a control diet, containing only α-linolenic acid (ALA) as ω-3 PUFAs. The shorter immobility times were observed in both male and female mice. A dopamine metabolite, 3,4-dihydroxyphenylacetic acid, increased in the NAc in male mice fed the KO diet when compared with those fed the control diet. In addition, dopamine, 3-methoxytyramine, and homovanillic acid increased in the NAc in female mice fed the KO diet. Notably, the effects of the KO diet on the immobility time in the FST were abolished by microinjection of sulpiride, an antagonist of D2-like receptors, into the NAc. A similar microinjection of an antagonist selective for D1-like receptors, SKF83566, also abolished the reduction in immobility in the FST. Moreover, we found that tyrosine hydroxylase-positive cells increased in the ventral tegmental area (VTA) in mice fed the KO diet. These results suggest that modulation of the VTA-NAc dopaminergic pathway is one of the mechanisms by which a KO diet rich in ω-3 PUFAs reduces the immobility behavior in the mouse FST.
Highlights
In the mammalian brain, long-chain polyunsaturated fatty acids (PUFAs) are major plasma membrane components affecting membrane fluidity [1, 2]
Female mice fed a Krill oil (KO) diet for 6 weeks showed less immobility time (t [18] = 2.117, p = 0.048, r = 0.45 n = 10 for each group) and the 8-week feeding group exhibited a reduction in immobility time (t [19] = 4.804, p < 0.001, r = 0.74; control, n = 10; KO, n = 11) compared to female mice fed a control diet, whereas the effects were not observed in the 2-week feeding group (t [18] = 1.083, p = 0.293, r = 0.25, n = 10 for each group) and 4 week feeding group (U [10, 10] = 38, p = 0.382, r = 0.20)
To compare the effect size, male mice in the 4-week and 6-week feeding group showed a large effect, while the female 6-week and 8-week feeding groups showed a medium and large effect, respectively. These results suggest that ω-3 PUFA supplementation reduces immobility time in both male and female mice in a time-dependent feeding manner
Summary
Long-chain polyunsaturated fatty acids (PUFAs) are major plasma membrane components affecting membrane fluidity [1, 2]. A large body of evidence has shown the beneficial effects of ω-3 PUFAs on human health [4,5,6]. An overall beneficial effect of ω-3 PUFA supplementation on major depressive disorders has been suggested by various clinical studies investigating the role of ω-3 PUFAs in the treatment of depression [7,8,9,10], and a recent meta-analysis involving 1 233 participants from 13 studies presented similar results [11]. Publication bias has been pointed out in one study [12], and the mechanisms underlying the effect of ω-3 PUFAs on depression are still unclear
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