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.
Highlights
Major depression and anxiety disorders are highly prevalent diseases that rank among the leading causes of disability worldwide.[1,2,3] The negative impact of these disorders is exacerbated by the poor remission rates obtained with standard treatments.[4]
Antidepressant effects have been hypothesized to result from the correction of endogenous 5-HT deficiency,[9] but recent studies have shown that mutant forms of the 5-HT synthesis gene, tryptophan hydroxylase 2 (Tph2),[10,11] which could result in impaired 5-HT synthesis,[12] are associated with poor antidepressant treatment responses.[13,14,15]
This would be consistent with prior work that has implicated variants in Tph[2] in antidepressant sensitivity in humans[14,15] and with prior preclinical work showing that acute pharmacologic inhibition of 5-HT synthesis blocks the acute effects of selective serotonin reuptake inhibitors (SSRIs) in the TST29 and forced swim test[30,31,32] in rodents
Summary
Major depression and anxiety disorders are highly prevalent diseases that rank among the leading causes of disability worldwide.[1,2,3] The negative impact of these disorders is exacerbated by the poor remission rates obtained with standard treatments.[4]. Antidepressant effects have been hypothesized to result from the correction of endogenous 5-HT deficiency,[9] but recent studies have shown that mutant forms of the 5-HT synthesis gene, tryptophan hydroxylase 2 (Tph2),[10,11] which could result in impaired 5-HT synthesis,[12] are associated with poor antidepressant treatment responses.[13,14,15] These observations suggest that congenital brain 5-HT deficiency might reduce antidepressant efficacy. Our results suggest that 5-HT deficiency can impair a subset of antidepressant effects and indicate that antidepressant-like effects in the NSF do not require antidepressant-induced increases in hippocampal neurogenesis, at least under conditions of congenital 5-HT deficiency
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