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The effects of congenital brain serotonin deficiency on responses to chronic fluoxetine.

Sachs BD, Jacobsen JP, Thomas TL, Siesser WB, Roberts WL, Caron MG - Transl Psychiatry (2013)

Bottom Line: These results suggest that inducing supra-physiological levels of 5-HT, not merely reversing 5-HT deficiency, is required for many of the antidepressant-like effects of FLX.Thus, our results indicate that brain 5-HT deficiency reduces the efficacy of FLX and that supplementation with 5-HTP can restore some antidepressant-like responses in the context of 5-HT deficiency.Our findings also suggest that feeding latency reductions in the NSF induced by chronic 5-HT elevation are not mediated by drug-induced increments in neurogenesis in 5-HT-deficient animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Duke University, Durham, NC 27710, USA.

ABSTRACT
The importance of reversing brain serotonin (5-HT) deficiency and promoting hippocampal neurogenesis in the mechanisms of action for antidepressants remain highly controversial. Here we examined the behavioral, neurochemical and neurogenic effects of chronic fluoxetine (FLX) in a mouse model of congenital 5-HT deficiency, the tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mouse. Our results demonstrate that congenital 5-HT deficiency prevents a subset of the signature molecular, cellular and behavioral effects of FLX, despite the fact that FLX restores the 5-HT levels of Tph2KI mice to essentially the levels observed in wild-type mice at baseline. These results suggest that inducing supra-physiological levels of 5-HT, not merely reversing 5-HT deficiency, is required for many of the antidepressant-like effects of FLX. We also demonstrate that co-administration of the 5-HT precursor, 5-hydroxytryptophan (5-HTP), along with FLX rescues the novelty suppressed feeding (NSF) anxiolytic-like effect of FLX in Tph2KI mice, despite still failing to induce neurogenesis. Thus, our results indicate that brain 5-HT deficiency reduces the efficacy of FLX and that supplementation with 5-HTP can restore some antidepressant-like responses in the context of 5-HT deficiency. Our findings also suggest that feeding latency reductions in the NSF induced by chronic 5-HT elevation are not mediated by drug-induced increments in neurogenesis in 5-HT-deficient animals. Overall, these findings shed new light on the impact of 5-HT deficiency on responses to FLX and may have important implications for treatment selection in depression and anxiety disorders.

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Effects of chronic fluoxetine (FLX) treatment on neurogenesis in wild-type (WT) and tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mice.Representative bromodeoxyuridine (BrdU)-stained micrographs of WT control (a), Tph2KI control (b), WT FLX (c) and Tph2KI FLX hippocampus (HIP) (d) are shown with quantifications shown in panel e. Arrows denote BrdU+ cells. Representative doublecortin (DCX)-stained micrographs of WT control (f), Tph2KI control (g), WT FLX (h) and Tph2KI FLX (i). Quantification of immunohistochemistry (IHC) for DCX is shown (j). Data were analyzed by two-way analysis of variance (ANOVA) followed by Tukey's post-hoc tests to compare individual differences. ‘X' denotes interaction between treatment and genotype (P<0.05) by two-way ANOVA. *Significant main effect of genotype (P<0.05). **P<0.05 compared with WT control by Tukey's post-hoc test; n=10–11 per group for a–e and n=12–14 per group for f–j. The scale bar indicates 20 μm.
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fig3: Effects of chronic fluoxetine (FLX) treatment on neurogenesis in wild-type (WT) and tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mice.Representative bromodeoxyuridine (BrdU)-stained micrographs of WT control (a), Tph2KI control (b), WT FLX (c) and Tph2KI FLX hippocampus (HIP) (d) are shown with quantifications shown in panel e. Arrows denote BrdU+ cells. Representative doublecortin (DCX)-stained micrographs of WT control (f), Tph2KI control (g), WT FLX (h) and Tph2KI FLX (i). Quantification of immunohistochemistry (IHC) for DCX is shown (j). Data were analyzed by two-way analysis of variance (ANOVA) followed by Tukey's post-hoc tests to compare individual differences. ‘X' denotes interaction between treatment and genotype (P<0.05) by two-way ANOVA. *Significant main effect of genotype (P<0.05). **P<0.05 compared with WT control by Tukey's post-hoc test; n=10–11 per group for a–e and n=12–14 per group for f–j. The scale bar indicates 20 μm.

Mentions: After observing no significant effects of FLX on cell survival, we next examined the effects of FLX on cell proliferation. No significant main effects of chronic FLX treatment or genotype were observed on BrdU incorporation. However, a significant genotype by treatment interaction was observed (F(1,37)=5.5383, P=0.024, Figures 3a–e). As expected,6 chronic treatment with FLX before BrdU administration increased the number of BrdU+ cells in WT mice (P=0.0259, Figures 3a, c and e). However, this treatment had no effect on BrdU incorporation in Tph2KI animals (Figures 3b, d and e).


The effects of congenital brain serotonin deficiency on responses to chronic fluoxetine.

Sachs BD, Jacobsen JP, Thomas TL, Siesser WB, Roberts WL, Caron MG - Transl Psychiatry (2013)

Effects of chronic fluoxetine (FLX) treatment on neurogenesis in wild-type (WT) and tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mice.Representative bromodeoxyuridine (BrdU)-stained micrographs of WT control (a), Tph2KI control (b), WT FLX (c) and Tph2KI FLX hippocampus (HIP) (d) are shown with quantifications shown in panel e. Arrows denote BrdU+ cells. Representative doublecortin (DCX)-stained micrographs of WT control (f), Tph2KI control (g), WT FLX (h) and Tph2KI FLX (i). Quantification of immunohistochemistry (IHC) for DCX is shown (j). Data were analyzed by two-way analysis of variance (ANOVA) followed by Tukey's post-hoc tests to compare individual differences. ‘X' denotes interaction between treatment and genotype (P<0.05) by two-way ANOVA. *Significant main effect of genotype (P<0.05). **P<0.05 compared with WT control by Tukey's post-hoc test; n=10–11 per group for a–e and n=12–14 per group for f–j. The scale bar indicates 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756292&req=5

fig3: Effects of chronic fluoxetine (FLX) treatment on neurogenesis in wild-type (WT) and tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mice.Representative bromodeoxyuridine (BrdU)-stained micrographs of WT control (a), Tph2KI control (b), WT FLX (c) and Tph2KI FLX hippocampus (HIP) (d) are shown with quantifications shown in panel e. Arrows denote BrdU+ cells. Representative doublecortin (DCX)-stained micrographs of WT control (f), Tph2KI control (g), WT FLX (h) and Tph2KI FLX (i). Quantification of immunohistochemistry (IHC) for DCX is shown (j). Data were analyzed by two-way analysis of variance (ANOVA) followed by Tukey's post-hoc tests to compare individual differences. ‘X' denotes interaction between treatment and genotype (P<0.05) by two-way ANOVA. *Significant main effect of genotype (P<0.05). **P<0.05 compared with WT control by Tukey's post-hoc test; n=10–11 per group for a–e and n=12–14 per group for f–j. The scale bar indicates 20 μm.
Mentions: After observing no significant effects of FLX on cell survival, we next examined the effects of FLX on cell proliferation. No significant main effects of chronic FLX treatment or genotype were observed on BrdU incorporation. However, a significant genotype by treatment interaction was observed (F(1,37)=5.5383, P=0.024, Figures 3a–e). As expected,6 chronic treatment with FLX before BrdU administration increased the number of BrdU+ cells in WT mice (P=0.0259, Figures 3a, c and e). However, this treatment had no effect on BrdU incorporation in Tph2KI animals (Figures 3b, d and e).

Bottom Line: These results suggest that inducing supra-physiological levels of 5-HT, not merely reversing 5-HT deficiency, is required for many of the antidepressant-like effects of FLX.Thus, our results indicate that brain 5-HT deficiency reduces the efficacy of FLX and that supplementation with 5-HTP can restore some antidepressant-like responses in the context of 5-HT deficiency.Our findings also suggest that feeding latency reductions in the NSF induced by chronic 5-HT elevation are not mediated by drug-induced increments in neurogenesis in 5-HT-deficient animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Duke University, Durham, NC 27710, USA.

ABSTRACT
The importance of reversing brain serotonin (5-HT) deficiency and promoting hippocampal neurogenesis in the mechanisms of action for antidepressants remain highly controversial. Here we examined the behavioral, neurochemical and neurogenic effects of chronic fluoxetine (FLX) in a mouse model of congenital 5-HT deficiency, the tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mouse. Our results demonstrate that congenital 5-HT deficiency prevents a subset of the signature molecular, cellular and behavioral effects of FLX, despite the fact that FLX restores the 5-HT levels of Tph2KI mice to essentially the levels observed in wild-type mice at baseline. These results suggest that inducing supra-physiological levels of 5-HT, not merely reversing 5-HT deficiency, is required for many of the antidepressant-like effects of FLX. We also demonstrate that co-administration of the 5-HT precursor, 5-hydroxytryptophan (5-HTP), along with FLX rescues the novelty suppressed feeding (NSF) anxiolytic-like effect of FLX in Tph2KI mice, despite still failing to induce neurogenesis. Thus, our results indicate that brain 5-HT deficiency reduces the efficacy of FLX and that supplementation with 5-HTP can restore some antidepressant-like responses in the context of 5-HT deficiency. Our findings also suggest that feeding latency reductions in the NSF induced by chronic 5-HT elevation are not mediated by drug-induced increments in neurogenesis in 5-HT-deficient animals. Overall, these findings shed new light on the impact of 5-HT deficiency on responses to FLX and may have important implications for treatment selection in depression and anxiety disorders.

Show MeSH
Related in: MedlinePlus