The effects of congenital brain serotonin deficiency on responses to chronic fluoxetine.
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.
Department of Cell Biology, Duke University, Durham, NC 27710, USA.
B D
BD
Sachs
J P R
JP
Jacobsen
T L
TL
Thomas
W B
WB
Siesser
W L
WL
Roberts
M G
MG
Caron
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001007:Anxiety / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis; D055495:Neurogenesis / Q000187:drug effects*; D012701:Serotonin / Q000172:deficiency* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014365:Tryptophan Hydroxylase / Q000235:genetics
D006916:5-Hydroxytryptophan; D018687:Antidepressive Agents, Second-Generation; D005473:Fluoxetine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D014365:Tryptophan Hydroxylase; C487802:Tph2 protein, mouse