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1. Fluoxetine exerts age-dependent effects on behavior and amygdala neuroplasticity in the rat.

Author

Judith R Homberg, Jocelien D A Olivier, Tom Blom, Tim Arentsen, Chantal van Brunschot, Pieter Schipper, Gerdien Korte-Bouws, Gilles van Luijtelaar, and Liesbeth Reneman

Subjects
Medicine, Science
Abstract

The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg) at postnatal day (PND) 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7-14 days after the last injection when (nor)fluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (nor)fluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling) immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT(1A) receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential fluoxetine-induced neuroplasticity in the amygdala.

Published
2011
Full Text
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2. Fluoxetine exerts age-dependent effects on behavior and amygdala neuroplasticity in the rat

Author

Pieter Schipper, Tom Blom, Jocelien D A Olivier, Gerdien A.H. Korte-Bouws, Judith R. Homberg, Liesbeth Reneman, Tim Arentsen, Chantal van Brunschot, Gilles van Luijtelaar, Amsterdam Neuroscience, Amsterdam Public Health, Radiology and Nuclear Medicine, and Faculteit der Geneeskunde

Subjects
Psychopharmacology, lcsh:Medicine, Biochemistry, Open field, Behavioral Neuroscience, Adolescent Psychiatry, lcsh:Science, Psychiatry, Multidisciplinary, Neuronal Plasticity, Behavior, Animal, Depression, Age Factors, Neurochemistry, Animal Models, Amygdala, Mental Health, Neurology, Behavioral Pharmacology, Antidepressant, Antidepressive Agents, Second-Generation, Medicine, Neurochemicals, Functional Neurogenomics [DCN 2], medicine.drug, Research Article, medicine.medical_specialty, Elevated plus maze, Drugs and Devices, Serotonin reuptake inhibitor, Biology, Dorsal raphe nucleus, Model Organisms, Neuropharmacology, Developmental Neuroscience, Internal medicine, Fluoxetine, medicine, Animals, Wakefulness, Depressive Disorder, Mood Disorders, Body Weight, lcsh:R, Rats, Endocrinology, Rat, lcsh:Q, Serotonin, Behavioural despair test, Neuroscience, Synaptic Plasticity
Abstract

Contains fulltext : 93695.pdf (Publisher’s version ) (Open Access) The selective serotonin reuptake inhibitor (SSRI) Prozac(R) (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg) at postnatal day (PND) 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7-14 days after the last injection when (nor)fluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (nor)fluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling) immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT(1A) receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential fluoxetine-induced neuroplasticity in the amygdala. 10 p.

Published
2011

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