Maternal fluoxetine reduces hippocampal inflammation and neurogenesis in adult offspring with sex-specific effects of periadolescent oxytocin.

Untreated perinatal depression can have severe consequences for the mother and her children. However, both the efficacy to mothers and safety to exposed infants of pharmacological antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been questioned. We previously reported that maternal SSRI exposure increased hippocampal IL-1ß levels, which may be tied to limited efficacy of SSRIs during the postpartum to the dam but is not yet known whether maternal postpartum SSRIs affect the neuroinflammatory profile of adult offspring. In addition, although controversial, perinatal SSRI exposure has been linked to increased risk of autism spectrum disorder (ASD) in children. Oxytocin (OT) is under investigation as a treatment for ASD, but OT is a large neuropeptide that has difficulty crossing the blood-brain barrier (BBB). TriozanTM is a nanoformulation that can facilitate OT to cross the BBB. Thus, we investigated the impact of maternal postpartum SSRIs and offspring preadolescent OT treatment on adult offspring neuroinflammation, social behavior, and neurogenesis in the hippocampus. Using a model of de novo postpartum depression, corticosterone (CORT) was given in the postpartum to the dam with or without treatment with the SSRI, fluoxetine (FLX) for 21 days postpartum. Offspring were then subsequently treated with either OT, OT + TriozanTM, or vehicle for 10 days prior to adolescence (PD25-34). Maternal FLX decreased hippocampal IL-10 and IL-13 and neurogenesis in both sexes, whereas maternal CORT increased hippocampal IL-13 in both sexes. Maternal CORT treatment shifted the neuroimmune profile towards a more proinflammatory profile in offspring hippocampus, whereas oxytocin, independent of formulation, normalized this profile. OT treatment increased hippocampal neurogenesis in adult males but not in adult females, regardless of maternal treatment. OT treatment increased the time spent with a novel social stimulus animal (social investigation) in both adult male and female offspring, although this effect depended on maternal CORT. These findings underscore that preadolescent exposure to OT can reverse some of the long-lasting effects of postpartum maternal CORT and FLX treatments in the adult offspring. In addition, we found that maternal treatments that reduce (CORT) or increase (FLX) hippocampal inflammation in dams resulted in opposing patterns of hippocampal inflammation in adult offspring.

Postpartum corticosterone and fluoxetine shift the tryptophan-kynurenine pathway in dams.

Perinatal depression (PND) affects 15% of mothers. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line of treatment for PND but are not always efficacious. Previously, we found significant reductions in plasma tryptophan concentrations and higher hippocampal proinflammatory cytokine, IL-1ß levels, due to maternal SSRI treatment. Both inflammation and tryptophan-kynurenine metabolic pathway (TKP) are associated with SSRI efficacy in individuals with major depressive disorder (MDD). TKP is divided into neuroprotective and neurotoxic pathways. Higher metabolite concentrations of the neurotoxic pathway are associated with depression onset and implicated in SSRI efficacy. Metabolites in TKP were investigated in a rodent model of de novo postpartum depression (PPD) given treatment with the SSRI, fluoxetine (FLX). Dams were administered corticosterone (CORT) (40 mg/kg, s.c.), and treated with the SSRI, fluoxetine (FLX) (10 mg/kg, s.c.), during the postpartum for 22 days after parturition. Plasma TKP metabolite concentrations were quantified on the last day of treatment. Maternal postpartum CORT increased neurotoxic metabolites and co-enzyme/cofactors in dams (3-hydroxykynurenine, 3-hydroxyanthranilic acid, vitamin B2, flavin adenine dinucleotide). The combination of both CORT and FLX shifted the neuroprotective-to-neurotoxic ratio towards neurotoxicity. Postpartum FLX decreased plasma xanthurenic acid concentrations. Together, our data indicate higher neurotoxic TKP expression due to maternal postpartum CORT treatment, similar to clinical presentation of MDD. Moreover, maternal FLX treatment showed limited efficacy to influence TKP metabolites, which may correspond to its limited efficacy to treat depressive-like endophenotypes in the postpartum. Overall suggesting changes in TKP may be used as a biomarker of de novo PPD and antidepressant efficacy and targeting this pathway may serve as a potential therapeutic target.

Postpartum fluoxetine increased maternal inflammatory signalling and decreased tryptophan metabolism: Clues for efficacy.

Perinatal depression (PND) affects approximately 15% of women, and de novo postpartum depression affects approximately 40% of PND cases. Selective serotonin reuptake inhibitors (SSRIs) are a common class of antidepressants prescribed to treat PND. However, the safety and efficacy of SSRIs have been questioned in both clinical and preclinical research. Here, using a preclinical rodent model of de novo postpartum depression, we aim to better understand neuroinflammatory cytokines and tryptophan mechanisms that may be related to SSRI efficacy. Rat dams were treated with high corticosterone (CORT; 40 mg/kg, s.c.) for 22 days in the postpartum period to simulate a depressive-like endophenotype. Concurrently, a subset of dams was treated with the SSRI, fluoxetine (FLX; 10 mg/kg, s.c.), in the postpartum period. We showed, consistent with previous studies, that although maternal FLX treatment prevented CORT-induced disturbances in maternal care behavior during the early postpartum, it failed to prevent the expression of CORT-induced passive coping behavior in the late postpartum. Furthermore, FLX treatment, regardless of CORT treatment, increased maternal hippocampal IL-1ß, plasma CXCL1, and decreased maternal plasma tryptophan, 4'-pyridoxic acid, and pyridoxal concentrations. Maternal CORT treatment reduced maternal hippocampal IFN-γ, and both hippocampal and plasma TNF-α. Our work suggests that the limited efficacy of FLX in the late postpartum may be associated with elevated levels of the proinflammatory cytokine IL-1ß in the maternal hippocampus, elevated plasma CXCL1, decreased plasma tryptophan concentration, and changes in vitamin B6 dependent tryptophan-kynurenine pathway. These findings suggest novel pathways for improving SSRI efficacy in alleviating perinatal depression.

Oxytocin has sex-specific effects on social behaviour and hypothalamic oxytocin immunoreactive cells but not hippocampal neurogenesis in adult rats.

Oxytocin regulates social behaviours, pair bonding and hippocampal neurogenesis but most studies have used adult males. Our study investigated the effects of oxytocin on social investigation and adult hippocampal neurogenesis in male and female rats. Oxytocin has poor penetration of the blood-brain barrier, therefore we tested a nanoparticle drug, TRIOZAN™ (Ovensa Inc.), which permits greater blood-brain-barrier penetration. Adult male and female rats were injected daily (i.p.) for 10 days with either: oxytocin in PBS (0.5 or 1.0 mg/kg), oxytocin in TRIOZAN™ (0.5 or 1.0 mg/kg), or vehicle (PBS) and tested for social investigation. Oxytocin decreased body mass and increased social investigation and number of oxytocin-immunoreactive cells in the supraoptic nucleus (SON) of the hypothalamus in male rats only. In both sexes, oxytocin decreased the number of immature neurons (doublecortin+ cells) in the ventral hippocampus and reduced plasma 17ß-estradiol levels in a dose- and delivery-dependent way. Oxytocin in TRIOZAN™ reduced "sedation" observed post-injection and increased certain central effects (oxytocin levels in the hypothalamus and neurogenesis in the ventral hippocampus) relative to oxytocin in PBS, indicating that the nanoparticle may be used as an alternative brain delivery system. We showed that oxytocin has sex-specific effects on social investigation, body mass, "sedation", and the oxytocin system. In contrast, similar effects were observed in both sexes in neurogenesis and plasma 17ß-estradiol. Our work suggests that sex differences in oxytocin regulation of brain endpoints is region-specific (hypothalamus versus hippocampus) and that oxytocin does not promote social investigation in females.