SummaryDecreased tissue levels of docosahexaenoic acid (DHA; 22:6n-3) are implicated in the etiologies of non-puerperal and postpartum depression. With the aim of determining neurobiological sequelae of decreased brain DHA content, this study examined the effects of a loss of brain DHA content and concurrent reproductive status in adult female Long-Evans rats. An α-linolenic acid-deficient diet and breeding protocols were used to produce virgin and parous female rats with cortical phospholipid DHA levels 23-26% lower than virgin and parous rats fed a control diet containing adequate α-linolenic acid. Parous dams were tested/euthanized at weaning (postnatal day 20) of the second litter; virgin females, during diestrus. Decreased brain DHA was associated with decreased hippocampal BDNF gene expression and increased relative corticosterone response to an intense stressor, regardless of reproductive status. In virgin females with decreased brain DHA, serotonin content and turnover in frontal cortex were decreased compared to virgin females with normal brain DHA. In parous dams with decreased brain DHA, the density of 5-HT 1A receptors in the hippocampus was increased, corticosterone response to an intense stressor was increased, and the latency to immobility in the forced swim test was decreased compared to parous dams with normal DHA. These findings demonstrate neurobiological alterations attributable to decreased brain DHA or an interaction of parous status and brain DHA level. Furthermore, the data are consistent with findings in depressed humans, and thus support a role for DHA as a factor in the etiologies of depressive illnesses, particularly postpartum depression.

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Low tissue levels of (n-3) PUFA, particularly docosahexaenoic acid [DHA, 22:6(n-3)], are implicated in postpartum depression. Brain DHA content is depleted in female rats undergoing pregnancy and lactation when the diet supplies inadequate (n-3) PUFA. In this study, the effects of DHA depletion as a result of reproductive activity and an (n-3) PUFA-deficient diet were examined in 8 specific brain regions of female rats after undergoing 2 sequential reproductive cycles. Virgin females, fed the alpha-linolenic acid (ALA)-containing or deficient (low-ALA) diets for a commensurate duration (13 wk) served as a control for reproduction. Total phospholipid composition of each brain region was determined at weaning (postnatal d 21) by TLC/GC. The regional PUFA composition of ALA virgins was similar to that previously measured in male rats. All brain regions examined were affected by reproductive activity and/or the low-ALA diet; however, the magnitude of the loss of DHA and compensatory incorporation of docosapentaenoic acid [(n-6) DPA, 22:5(n-6)] varied among brain regions. In low-ALA parous dams, frontal cortex (77% of ALA virgin) and temporal lobe (83% of ALA virgin), regions involved in cognition and affect, were among those exhibiting the greatest depletion of DHA. Caudate-putamen also exhibited significant depletion of DHA (82% of ALA virgin), whereas only (n-6) DPA levels were altered in ventral striatum, hypothalamus, hippocampus, and cerebellum. This pattern of changes in regional DHA and (n-6) DPA content suggests that specific neuronal systems may be differentially affected by depletion of brain DHA in the postpartum organism.

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Glycine N-methyltransferase (GNMT) regulates the methyl group supply for S-adenosylmethionine-dependent transmethylation reactions. Retinoids have been shown to perturb methyl group metabolism by increasing the abundance and activity of GNMT, thereby leading to the loss of methyl groups. Previous studies used pharmacologic doses (30 micro mol/kg body weight) of various retinoids administered daily for a total of 10 d. Here, we examined the dose- and time-dependent relationships between all-trans-retinoic acid (ATRA) administration and induction of GNMT, as well as determining additional indices of methyl group and folate metabolism. For the dose-response study, rats were administered 0, 1, 5, 10, 15 or 30 micro mol ATRA/kg body weight for 10 d. For the time-course study, rats were given 30 micromol ATRA/kg body weight for 0, 1, 2, 4, or 8 d. A significant increase (105%) in GNMT activity was observed with doses as low as 5 micromol/kg body weight, whereas maximal induction (231%) of GNMT activity was achieved at 30 micromol/kg body weight. Induction of hepatic GNMT by ATRA was rapid, exhibiting a 31% increase after a single dose (1 d) and achieving maximal induction (95%) after 4 d. Plasma methionine and homocysteine concentrations were decreased 42 and 53%, respectively, in ATRA-treated rats compared with controls. In support of this finding, the hepatic activity of methionine synthase, the folate-dependent enzyme required for homocysteine remethylation, was elevated 40% in ATRA-treated rats. This work demonstrates that ATRA administration exerts a rapid effect on hepatic methyl group, folate and homocysteine metabolism at doses that are within the therapeutic range used by humans.