Fluoxetine Exerts Age-Dependent Effects on Behavior and Amygdala Neuroplasticity in the Rat

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-HT1A 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.

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

“…However, since we did not measure drug plasma concentrations we cannot be certain that differences in plasma concentrations underlie the different findings in the three experiments: "only" a treatment effect on behavioral studies and phMRI, whereas an interacting effect of age and treatment on the binding assays. In line with this, at higher oral concentrations of 12 mg/kg fluoxetine age-related treatment effects have been noted on behavior (Homberg et al 2011).…”

Increased Aggression, Improved Spatial Memory, and Reduced Anxiety-Like Behaviour in Adult Male Mice Exposed to Fluoxetine Early in Life

“…Flx administered orally is detected in the blood plasma of the animal [42]. The ability of SSRIs, in particular Flx, to cross the placental barrier is similar in humans and animals [rats: [18]; mice: [23]; sheep: [43]].…”

Modulation of Neural Plasticity as a Basis for Stroke Rehabilitation

“…57 In the postischemic brain, selective serotonin reuptake inhibitors are neuroprotective through their anti-inflammatory effects and improve ischemia-induced spatial cognitive deficits by promoting hippocampal neurogenesis in the rat. 58 A clinical study, fluoxetine for motor recovery after acute ischemic stroke (FLAME), demonstrated in a larger cohort of patients (nϭ118) with moderate to severe hemiplegia after ischemic stroke that physiotherapy in combination with early treatment with fluoxetine enhances motor recovery and reduces the number of dependent patients compared with physiotherapy alone. 59 These interesting results call for even larger and more comprehensive trials with an extended focus on functional outcome parameters.…”