Effects of Chronic Fluoxetine Treatment on Neurogenesis and Tryptophan Hydroxylase Expression in Adolescent and Adult Rats

Abstract

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.

Effects of early-life stress on cognitive function and hippocampal structure in female rodents

“…(Kempermann et al, 2006;Veenema et al, 2007b;Pawluski et al, 2009;Barha et al, 2011). While the numbers we found here were largely in line with studies on rats of related ages (Oomen et al, , 2011Klomp et al, 2014), MD did not affect neurogenesis in female rats 17 weeks of age, indicating that the decreased neurogenesis found earlier in MD females at PND 21 (Oomen et al, 2009) does not last into later ages. The same applies to the earlier found decrease in DG cell number and density measured at 10 weeks after MD at PND3 (Oomen et al, 2011), which was not maintained in the animals we collected around 17 weeks of age.…”

Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment

“…7, 42 However, recent data suggest that FLX may not be effective in enhancing neurogenesis 16, 17 or even reduce it. 16, 17, 18, 19, 43, 44 Similar contradictory results have been found for the effects of SSRI on hippocampal volumetric reduction, which is considered a further feature of depression. 45 Overall, we found that FLX has no effect on neurogenesis in the enriched condition, but leads to detrimental consequences on proliferation in the stressful condition (Figure 2a and b).…”

“…For instance, many studies show that SSRI administration reduces depression-like behavior, 5, 6 enhances neurogenesis, 7 increases brain-derived neurotrophic factor (BDNF) levels, 5, 8 reduces hypothalamic–pituitary–adrenal (HPA) axis activity 9, 10 and heightens long-term potentiation (LTP). 11 However, many others reported no or opposite effects concerning the same endpoints: behavior, 12, 13, 14, 15 neurogenesis, 16, 17, 18, 19, 20 BDNF levels, 21, 22, 23, 24, 25, 26 HPA axis activity 27, 28 and LTP. 29, 30 …”

Combination fluconazole/paroxetine treatment is neuroprotective despite ongoing neuroinflammation and viral replication in an SIV model of HIV neurological disease

“…In contrast, paroxetine and other SSRIs have proven neuroprotective in several animal models of neurodegenerative diseases (Chiou et al , 2006; Chung et al , 2010; Chung et al , 2011; Lim et al , 2009; Mattson et al , 2004; Nelson et al , 2007; Peng et al , 2008; Shibui et al , 2009). SSRI neuroprotection has been attributed to inhibition of neuroinflammation and oxidative stress (Chiou et al , 2006; Chung et al , 2010; Chung et al , 2011; Lim et al , 2009; Zhang et al , 2012), inhibition of apoptosis and promotion of neuroprotective BDNF signaling (Mattson et al , 2004), rescue or enhancement of neurogenesis (Jiang et al , 2014; Klomp et al , 2014; Lee et al , 2011; Stagni et al , 2013), and even inhibition of glutamate excitotoxicity (Vizi et al , 2013) in both animal models and cell culture, all of which have been implicated in the development of HAND (Lindl et al , 2010; Mocchetti et al , 2014; Potter et al , 2013; Steiner et al , 2006). In this study, we found FluPar treatment prevented neurodegeneration without significantly inhibiting multiple measures of neuroinflammation, indicating further investigation into the mechanism of action is needed.…”