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.

Physical exercise versus fluoxetine: Antagonistic effects on cortical spreading depression in Wistar rats

“…Regarding fluoxetine effects on body weight, our findings are in agreement with those of Klomp et al (2014) of no effect of fluoxetine treatment on weight gain in adolescent rats. Fluoxetine administration seems to reduce lab chow consumption during the first days of treatment, reaching a steady state after the first week (Gamaro et al, 2008).…”

Expression of 22 serotonin-related genes in rat brain after sub-acute serotonin depletion or reuptake inhibition

“…In line with these observations, raphe Tph2 expression was markedly reduced in rats exposed to paroxetine for 3 days. The TPH2 enzyme being downregulated by SSRIs has been shown before, both by means of histochemical methods (MacGillivray et al, 2010) and by means of assessment of mRNA expression (Dygalo et al, 2006;Abumaria et al, 2007;Shishkina et al, 2007;Klomp et al, 2014); however, a common view has been that such an effect requires weeks of treatment to be at hand (Dygalo et al, 2006). In contrast, our results suggest that increased extracellular serotonin levels in the raphe region leads to a downregulation of Tph2 that takes no more than 3 days to be manifest.…”

Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning

“…Although limited, previous work has found that dopamine levels in the medial PFC are increased after acute fluoxetine challenge in adolescent and adult male rats (Klomp et al, 2014) and that turnover ratios of HVA/DA in the striatum, PFC and amygdala are also increased in adult rats after early life maternal deprivation and in the hippocampus of adolescent male rats exposed to the forced swim test (Dalla et al, 2008;Rentesi et al, 2013). Although limited, previous work has found that dopamine levels in the medial PFC are increased after acute fluoxetine challenge in adolescent and adult male rats (Klomp et al, 2014) and that turnover ratios of HVA/DA in the striatum, PFC and amygdala are also increased in adult rats after early life maternal deprivation and in the hippocampus of adolescent male rats exposed to the forced swim test (Dalla et al, 2008;Rentesi et al, 2013).…”