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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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Neurochemical and behavioral responses to chronic fluoxetine (FLX) in wild-type (WT) and tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mice. (a) Levels of extracellular 5-HT (5-HTEXT) in the hippocampus (HIP) were determined by microdialysis. (b) Feeding latency in the novelty suppressed feeding (NSF) test after chronic FLX treatment. (c) Home-cage feeding latency in WT and Tph2KI mice following chronic FLX. (d) Feeding latency in the NSF after acute chlordiazepoxide administration. (e) Feeding latency in the NSF following chronic desipramine (DES) treatment in WT and Tph2KI mice. (f) Immobility time in the tail suspension test (TST) following chronic FLX. *Significant main effect of treatment by two-way analysis of variance (ANOVA; P<0.05). **P<0.05 compared with WT control by Tukey's post-hoc test. ^P<0.05 compared with WT FLX by Tukey's post-hoc test. @P<0.05 by Tukey's post-hoc test compared with control Tph2KI mice. ‘X' denotes a significant genotype by treatment interaction by two-way ANOVA (P<0.05) and ‘#' denotes a significant main effect of genotype (P<0.05 by two-way ANOVA); n=7–8 per group for a, n=19–21 per group for b, n=10 per group for c, n=9 per group for d, n=8–11 per group for e and n=22–27 per group for f.
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fig1: Neurochemical and behavioral responses to chronic fluoxetine (FLX) in wild-type (WT) and tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mice. (a) Levels of extracellular 5-HT (5-HTEXT) in the hippocampus (HIP) were determined by microdialysis. (b) Feeding latency in the novelty suppressed feeding (NSF) test after chronic FLX treatment. (c) Home-cage feeding latency in WT and Tph2KI mice following chronic FLX. (d) Feeding latency in the NSF after acute chlordiazepoxide administration. (e) Feeding latency in the NSF following chronic desipramine (DES) treatment in WT and Tph2KI mice. (f) Immobility time in the tail suspension test (TST) following chronic FLX. *Significant main effect of treatment by two-way analysis of variance (ANOVA; P<0.05). **P<0.05 compared with WT control by Tukey's post-hoc test. ^P<0.05 compared with WT FLX by Tukey's post-hoc test. @P<0.05 by Tukey's post-hoc test compared with control Tph2KI mice. ‘X' denotes a significant genotype by treatment interaction by two-way ANOVA (P<0.05) and ‘#' denotes a significant main effect of genotype (P<0.05 by two-way ANOVA); n=7–8 per group for a, n=19–21 per group for b, n=10 per group for c, n=9 per group for d, n=8–11 per group for e and n=22–27 per group for f.

Mentions: Consistent with our previous results,16, 17 microdialysis revealed that Tph2KI mice have reduced extracellular 5-HT (5-HTEXT) in the HIP compared with WT controls (main effect of genotype: F(1,25)=135.8074, P<0.0001, Figure 1a). Chronic treatment with FLX increased 5-HTEXT in both genotypes (main effect of FLX: F(1,25)=88.8577, P<0.0001, Figure 1a). However, the magnitude of the FLX-induced increase in 5-HTEXT in Tph2KI mice (∼2.25-fold, P=0.0326) was markedly less than that observed in WT animals (∼6.4-fold, genotype by drug interaction: F(1,25)=28.3908, P<0.0001, Figure 1a). Importantly, the levels of 5-HTEXT in Tph2KI mice after chronic FLX treatment were not significantly different from those in untreated WT mice (P=0.3963), but they were only 12% of the levels achieved in FLX-treated WT animals. These results suggest that although chronic FLX treatment essentially reverses hippocampal 5-HT deficiency in Tph2KI mice, congenital 5-HT deficiency can significantly blunt the neurochemical effects of selective serotonin reuptake inhibitors (SSRIs).


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)

Neurochemical and behavioral responses to chronic fluoxetine (FLX) in wild-type (WT) and tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mice. (a) Levels of extracellular 5-HT (5-HTEXT) in the hippocampus (HIP) were determined by microdialysis. (b) Feeding latency in the novelty suppressed feeding (NSF) test after chronic FLX treatment. (c) Home-cage feeding latency in WT and Tph2KI mice following chronic FLX. (d) Feeding latency in the NSF after acute chlordiazepoxide administration. (e) Feeding latency in the NSF following chronic desipramine (DES) treatment in WT and Tph2KI mice. (f) Immobility time in the tail suspension test (TST) following chronic FLX. *Significant main effect of treatment by two-way analysis of variance (ANOVA; P<0.05). **P<0.05 compared with WT control by Tukey's post-hoc test. ^P<0.05 compared with WT FLX by Tukey's post-hoc test. @P<0.05 by Tukey's post-hoc test compared with control Tph2KI mice. ‘X' denotes a significant genotype by treatment interaction by two-way ANOVA (P<0.05) and ‘#' denotes a significant main effect of genotype (P<0.05 by two-way ANOVA); n=7–8 per group for a, n=19–21 per group for b, n=10 per group for c, n=9 per group for d, n=8–11 per group for e and n=22–27 per group for f.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Neurochemical and behavioral responses to chronic fluoxetine (FLX) in wild-type (WT) and tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mice. (a) Levels of extracellular 5-HT (5-HTEXT) in the hippocampus (HIP) were determined by microdialysis. (b) Feeding latency in the novelty suppressed feeding (NSF) test after chronic FLX treatment. (c) Home-cage feeding latency in WT and Tph2KI mice following chronic FLX. (d) Feeding latency in the NSF after acute chlordiazepoxide administration. (e) Feeding latency in the NSF following chronic desipramine (DES) treatment in WT and Tph2KI mice. (f) Immobility time in the tail suspension test (TST) following chronic FLX. *Significant main effect of treatment by two-way analysis of variance (ANOVA; P<0.05). **P<0.05 compared with WT control by Tukey's post-hoc test. ^P<0.05 compared with WT FLX by Tukey's post-hoc test. @P<0.05 by Tukey's post-hoc test compared with control Tph2KI mice. ‘X' denotes a significant genotype by treatment interaction by two-way ANOVA (P<0.05) and ‘#' denotes a significant main effect of genotype (P<0.05 by two-way ANOVA); n=7–8 per group for a, n=19–21 per group for b, n=10 per group for c, n=9 per group for d, n=8–11 per group for e and n=22–27 per group for f.
Mentions: Consistent with our previous results,16, 17 microdialysis revealed that Tph2KI mice have reduced extracellular 5-HT (5-HTEXT) in the HIP compared with WT controls (main effect of genotype: F(1,25)=135.8074, P<0.0001, Figure 1a). Chronic treatment with FLX increased 5-HTEXT in both genotypes (main effect of FLX: F(1,25)=88.8577, P<0.0001, Figure 1a). However, the magnitude of the FLX-induced increase in 5-HTEXT in Tph2KI mice (∼2.25-fold, P=0.0326) was markedly less than that observed in WT animals (∼6.4-fold, genotype by drug interaction: F(1,25)=28.3908, P<0.0001, Figure 1a). Importantly, the levels of 5-HTEXT in Tph2KI mice after chronic FLX treatment were not significantly different from those in untreated WT mice (P=0.3963), but they were only 12% of the levels achieved in FLX-treated WT animals. These results suggest that although chronic FLX treatment essentially reverses hippocampal 5-HT deficiency in Tph2KI mice, congenital 5-HT deficiency can significantly blunt the neurochemical effects of selective serotonin reuptake inhibitors (SSRIs).

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