title: Increased response to a 5-HT challenge after discontinuation of chronic serotonin uptake inhibition in the adult and adolescent rat brain.
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.
authors.affiliation: Department of Radiology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Anne
authors.initials: A
authors.lastname: Klomp
authors.affiliation: Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands; Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Ralph
authors.initials: R
authors.lastname: Hamelink
authors.affiliation: Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands; Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Matthijs
authors.initials: M
authors.lastname: Feenstra
authors.affiliation: Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands; Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Damiaan
authors.initials: D
authors.lastname: Denys
authors.affiliation: Department of Radiology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Reneman
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D005473:Fluoxetine; D012701:Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors