Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats.
The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b) effects on tryptophan hydroxylase (TPH) expression, a measure of serotonin synthesis; c) whether treatment effects during adolescence differed from treatment at an adult age, and d) whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+) cells and of the number of young migratory neurons (doublecortin+), revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population.
Department of Radiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Anne
A
Klomp
Swammerdam Institute of Life Sciences, Centre for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
Lena
L
Václavů
Swammerdam Institute of Life Sciences, Centre for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
Gideon F
GF
Meerhoff
Department of Radiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Liesbeth
L
Reneman
Swammerdam Institute of Life Sciences, Centre for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
Paul J
PJ
Lucassen
D000367:Age Factors; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects* / Q000473:pathology; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005473:Fluoxetine / Q000009:adverse effects*; D015870:Gene Expression; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000096:biosynthesis; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
D018687:Antidepressive Agents, Second-Generation; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D005473:Fluoxetine; D012701:Serotonin; D014365:Tryptophan Hydroxylase