Age-dependent effects of chronic fluoxetine treatment on the serotonergic system one week following treatment

Bouët, Valentine; Klomp, Anne; Freret, Thomas; Wylezinska-Arridge, Marzena; Lopez-Tremoleda, Jordi; Dauphin, François; Boulouard, Michel; Booij, Jan; Gsell, Willy; Reneman, Liesbeth

doi:10.1007/s00213-011-2580-1

Cited by 30 publications

(22 citation statements)

References 43 publications

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“…In a previous study, we found FLX to increase anxiety-like behaviour in adult but not adolescent rats, which was paralleled by increased SERT densities in most cortical brain regions in the adolescent, but not adult, treated rats [66]. This indicated that effects of FLX on the 5-HT system are age-dependent [67], consistent with the present neurogenic effects in the developing brain that differ from those in the adult.…”

Section: Discussionsupporting

confidence: 86%

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

et al. 2014

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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.

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Section: Discussionsupporting

confidence: 86%

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

et al. 2014

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“…Of direct relevance to the findings presented here, two previous rat studies (5, 6) found that fluoxetine upregulated SERT in cortical regions by ~20% when administered during the juvenile period, but not during adulthood. Furthermore, fluoxetine exposure during early life—but not adulthood—produced delayed, persistent perturbations of emotional behaviors similar to those seen in mice lacking SERT (35, 36).…”

Section: Discussionsupporting

confidence: 80%

“…However, two previous studies in rats showed that fluoxetine has age-dependent effects and persistently upregulated SERT by ~20%, primarily in cortical regions, when administered during the juvenile period but not in adulthood (5, 6). A third limitation was that our PET study used ketamine to initially immobilize the monkeys; ketamine has widespread effects on glutamatergic transmission and induces rapid antidepressant effects in humans (43).…”

Section: Discussionmentioning

confidence: 96%

“…However, overwhelming evidence supports the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treating mood and anxiety disorders in this population (2). Nevertheless, studies on the use of SSRIs suggest transient, age-delimited effects on suicidal ideation (3, 4) as well as long-lasting effects on the developing brain in rodents (5, 6). These issues are particularly salient in humans as a result of the protracted development of the human brain (7, 8).…”

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confidence: 99%

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Fluoxetine Administered to Juvenile Monkeys: Effects on the Serotonin Transporter and Behavior

Shrestha

Nelson

Liow

et al. 2014

AJP

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Objective This study examined the long-term effects of fluoxetine administered to juvenile rhesus monkeys who, as young adults, were imaged with positron emission tomography for two serotonergic markers: serotonin transporter (SERT) and serotonin 1A (5-HT1A) receptor. An equal number of monkeys separated from their mothers at birth—an animal model of human childhood stress—were also studied. Method At birth, 32 male rhesus monkeys were randomly assigned to either maternal separation or normal rearing conditions. At age 2, half (N = 8) of each group was randomly assigned to fluoxetine (3 mg/kg) or placebo for 1 year. To eliminate the confounding effects of residual drug in the brain, monkeys were scanned at least 1.5 years after drug discontinuation. Social interactions were assessed both during and after drug administration. Results Fluoxetine persistently upregulated SERT, but not 5-HT1A receptors, in both the neocortex and the hippocampus. Whole-brain voxel-wise analysis revealed that fluoxetine had a significant effect in the lateral temporal and cingulate cortices. In contrast, neither maternal separation by itself nor the rearing-by-drug interaction was significant for either marker. Fluoxetine had no significant effect on the behavioral measures. Conclusions Fluoxetine administered to juvenile monkeys upregulates SERT into young adulthood. Implications regarding the efficacy or potential adverse effects of SSRIs in patients cannot be directly drawn from this study. Its purpose was to investigate effects of SSRIs on brain development in nonhuman primates using an experimental approach that randomly assigned long-term SSRI treatment or placebo.

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“…In both rodent and non-human primates, a prolonged upregulation of the serotonin transporter (SERT) has been found in cortex and hippocampus after juvenile or periadolescent fluoxetine treatment (8–10). Interestingly, in primates, no effects were observed on fear-related or social behaviors (8).…”

Section: Introductionmentioning

confidence: 99%

Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice

Dincheva

Yang

et al. 2017

AJP

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Objective Adolescence is a developmental stage in which the incidence of psychiatric disorders, such as anxiety disorders, peaks. Selective serotonin reuptake inhibitors (SSRIs) are the main class of agents used to treat anxiety disorders. However, the impact of SSRIs on the developing brain during adolescence remains unknown. The present study sought to determine the impact of developmentally-timed SSRI administration in a genetic mouse model displaying elevated anxiety-like behaviors. Method Knock-in mice containing a common human SNP (Val66Met; rs6265) in BDNF, a growth factor implicated in the mechanism of action of SSRIs, were studied based on their established phenotype of increased anxiety-like behavior. Timed administration of fluoxetine was delivered during one of three developmental periods (postnatal days (P)21–42, P40–61, or P60–81), spanning the transition from childhood to adulthood. Neurochemical and anxiety-like behavioral analyses were performed. Results We identified a “sensitive period” in peri-adolescence (P21–P42), in which developmentally-timed fluoxetine administration rescued anxiety-like phenotypes in BDNF Val66Met mice in adulthood. Compared to littermate controls, BDNFMet/Met mice exhibited diminished maturation of serotonergic fibers projecting particularly to the prefrontal cortex, as well as decreased expression of the serotonergic trophic factor S100B in the dorsal raphe. Interestingly, deficient serotonergic innervation, as well as S100B levels, were rescued with timed peri-adolescent fluoxetine administration. Conclusions Our findings suggest that SSRI administration during a peri-adolescent “sensitive period” leads to long-lasting anxiolytic effects in a genetic mouse model of elevated anxiety-like behaviors. These persistent effects highlight the role of BDNF in the maturation of the serotonin system, and the capacity to enhance its development through a pharmacological intervention.

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Age-dependent effects of chronic fluoxetine treatment on the serotonergic system one week following treatment

Cited by 30 publications

References 43 publications

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

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

Fluoxetine Administered to Juvenile Monkeys: Effects on the Serotonin Transporter and Behavior

Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice

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