Abstract
Little is known about the effects of chronic fluoxetine on 5-HT transmission in the adolescent brain, even though it is acknowledged that the neuroplasticity of the brain during childhood and adolescence might influence the neurobiological mechanisms underlying treatment response. Also, possible ongoing effects on monoamine function following drug discontinuation are unidentified. We therefore examined the chronic effects of fluoxetine on extracellular 5-HT and dopamine concentrations in the medial prefrontal cortex and studied their responsiveness to an acute 5-HT challenge after a one-week washout period, both in adolescent and adult rats. Noradrenaline was measured in adult animals only. Fluoxetine increased 5-HT to 200–300% of control and DA and NA to 150% of control. Although there were no lasting effects of chronic fluoxetine on basal monoamine levels, we observed a clear potentiating effect of previous treatment on the fluoxetine-induced increase in extracellular 5-HT and, to a lesser extent, extracellular DA. No differential effect was found for noradrenaline. Age-at-treatment did not influence these results. So, after cessation of chronic fluoxetine treatment 5-HT responsiveness remains heightened. This may be indicative of the continuing presence of 5-HT receptor desensitization, at least until one week after drug discontinuation in rats. No apparent age-at-treatment effects on extracellular monoamine concentrations in the medial prefrontal cortex were detected, but age-related differences in 5-HT transmission further down-stream or in the recovery processes cannot be ruled out.
Highlights
The first onset of mood- and anxiety disorders usually occurs during adolescence
Prescription rates of psychotropic drugs such as antidepressants have increased significantly in the last 20 years among children and adolescents [3], indicating better recognition of childhood depression. This expansion is worrisome since the ongoing neuroplasticity of the brain during childhood and adolescence might influence the neurobiological mechanisms underlying treatment response [4]
The efficacy of selective serotonin (5-HT) reuptake inhibitors (SSRIs) in the treatment of pediatric depression is still disputed [5,6,7,8,9] while tricyclic antidepressants have been shown to be ineffective [10]
Summary
The first onset of mood- and anxiety disorders usually occurs during (early) adolescence. Clinical studies have raised concerns about increases in suicidal ideation and behavior in children and adolescents treated with SSRIs [11,12,13] and increased agitation, depression and anxiety [12] as well as negative effects on growth rate [14] have been described. This apparent heightened sensitivity to adverse effects has even led to governmental warnings on the use of antidepressants in youngsters. The SSRI fluoxetine (FLX) was recently approved by the same governmental institutions for the treatment of childhood depression in children of 8 years and older
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