Limits...
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.

Show MeSH

Related in: MedlinePlus

A quantification of double immunofluorescence for bromodeoxyuridine (BrdU) and NeuN in wild-type (WT) and tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mice. (a) The average percentage of BrdU+ cells that are also NeuN+. (b) The average total number of BrdU+ and (c) the average total number of BrdU+/NeuN+ cells in control and fluoxetine (FLX)-treated WT and Tph2KI mice. Representative micrographs from control WT (d), control Tph2KI (e), FLX-treated WT (f) and FLX-treated Tph2KI (g) are shown. Higher magnification images of the indicated area in e reveal a BrdU+ and an adjacent BrdU+/NeuN+ cell (h, i). TOTO-3+ nuclei are shown in blue, NeuN is shown in green and BrdU is shown in red. The scale bar indicates 20 μm for d–g and 10 μm for h and i. *Significant main effect of genotype P<0.05, n=6 per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3756292&req=5

fig4: A quantification of double immunofluorescence for bromodeoxyuridine (BrdU) and NeuN in wild-type (WT) and tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mice. (a) The average percentage of BrdU+ cells that are also NeuN+. (b) The average total number of BrdU+ and (c) the average total number of BrdU+/NeuN+ cells in control and fluoxetine (FLX)-treated WT and Tph2KI mice. Representative micrographs from control WT (d), control Tph2KI (e), FLX-treated WT (f) and FLX-treated Tph2KI (g) are shown. Higher magnification images of the indicated area in e reveal a BrdU+ and an adjacent BrdU+/NeuN+ cell (h, i). TOTO-3+ nuclei are shown in blue, NeuN is shown in green and BrdU is shown in red. The scale bar indicates 20 μm for d–g and 10 μm for h and i. *Significant main effect of genotype P<0.05, n=6 per group.

Mentions: We next performed double-labeling experiments to compare the percentage of BrdU+ cells that become NeuN+ neurons between the groups. In both WT and Tph2KI animals, ∼80% of the BrdU+ cells in the GCL were also immunopositive for NeuN 3 weeks after a 1-week exposure to BrdU, and FLX administration did not significantly affect the proportion of BrdU+/NeuN+ cells in either genotype (Figure 4a). We again observed a significant increase in the number of surviving BrdU+ cells in Tph2KI mice compared with WT animals (main effect of genotype: F(1,20)=5.3493, P=0.0315, Figure 4b). Similarly, the total number of BrdU+/NeuN+ neurons was greater in Tph2KI than in WT animals (main effect of genotype: F(1,20)=5.5470, P=0.0288, Figure 4c). Representative images are shown in Figures 4 d–i.


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)

A quantification of double immunofluorescence for bromodeoxyuridine (BrdU) and NeuN in wild-type (WT) and tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mice. (a) The average percentage of BrdU+ cells that are also NeuN+. (b) The average total number of BrdU+ and (c) the average total number of BrdU+/NeuN+ cells in control and fluoxetine (FLX)-treated WT and Tph2KI mice. Representative micrographs from control WT (d), control Tph2KI (e), FLX-treated WT (f) and FLX-treated Tph2KI (g) are shown. Higher magnification images of the indicated area in e reveal a BrdU+ and an adjacent BrdU+/NeuN+ cell (h, i). TOTO-3+ nuclei are shown in blue, NeuN is shown in green and BrdU is shown in red. The scale bar indicates 20 μm for d–g and 10 μm for h and i. *Significant main effect of genotype P<0.05, n=6 per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: A quantification of double immunofluorescence for bromodeoxyuridine (BrdU) and NeuN in wild-type (WT) and tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mice. (a) The average percentage of BrdU+ cells that are also NeuN+. (b) The average total number of BrdU+ and (c) the average total number of BrdU+/NeuN+ cells in control and fluoxetine (FLX)-treated WT and Tph2KI mice. Representative micrographs from control WT (d), control Tph2KI (e), FLX-treated WT (f) and FLX-treated Tph2KI (g) are shown. Higher magnification images of the indicated area in e reveal a BrdU+ and an adjacent BrdU+/NeuN+ cell (h, i). TOTO-3+ nuclei are shown in blue, NeuN is shown in green and BrdU is shown in red. The scale bar indicates 20 μm for d–g and 10 μm for h and i. *Significant main effect of genotype P<0.05, n=6 per group.
Mentions: We next performed double-labeling experiments to compare the percentage of BrdU+ cells that become NeuN+ neurons between the groups. In both WT and Tph2KI animals, ∼80% of the BrdU+ cells in the GCL were also immunopositive for NeuN 3 weeks after a 1-week exposure to BrdU, and FLX administration did not significantly affect the proportion of BrdU+/NeuN+ cells in either genotype (Figure 4a). We again observed a significant increase in the number of surviving BrdU+ cells in Tph2KI mice compared with WT animals (main effect of genotype: F(1,20)=5.3493, P=0.0315, Figure 4b). Similarly, the total number of BrdU+/NeuN+ neurons was greater in Tph2KI than in WT animals (main effect of genotype: F(1,20)=5.5470, P=0.0288, Figure 4c). Representative images are shown in Figures 4 d–i.

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