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Involvement of BDNF in fluoxetine-induced changes in body weight: studies in Wistar Zagreb-5HT rat model

Introduction: There is an evidence that antidepressant (AD) drug therapy is associated with significant changes in body weight. Due to increasing rates of obesity and the fact that AD agents are among the most commonly prescribed drugs, the impact of their use on obesity risk is receiving much attention. The direction of the body weight change seems to be influence by the choice of AD drugs. In particular, it was shown that fluoxetine causes a weight loss and paroxetine causes a weight gain, although both drugs are selective serotonin reuptake inhibitors (SSRI) and act through increasing the amount of brain extracellular serotonin (5HT). These observations suggest involvement of other molecular pathways in mediating effects of these drugs on body weight control. Brain-derived neurotrophic factor (BDNF) is a well-known neurotrophin, highly expressed in hypothalamus and hippocampus, brain regions critically implicated in metabolic/endocrine and emotional/cognitive functions. BDNF has been implicated in eating behaviors and body weight regulation through modulation of the serotonergic pathways. It was shown that SSRIs induce upregulation of BDNF signalling. The possibility that 5HT and BDNF act synergistically to mediate the actions of AD drugs, including that related to changes in body weight, requires further investigation. Here we explored 5HT–BDNF systems interactions using an original genetic model of rats with constitutionally altered (hypo or hyper) serotonergic system. Methods: Male animals from hyperserotonergic (high-5HT) and hyposerotonergic (low-5HT) subline of the Wistar-Zagreb 5HT (WZ-5HT) rat model, obtained by selective breeding toward platelet 5HT transporter activity, were treated with fluoxetine (6 mg/kg, i.p) for 27 days. During treatment, body weight of animals was monitored daily. Hippocampal BDNF mRNA and protein levels were assessed 48 h after the last injection, using reverse transciption-quantitative polymerase chain reaction (RT- qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Results: As expected, animals treated with fluoxetine showed less weight gain compared to non-treated animals ; no difference in this regard was observed between the sublines. Further, our results revealed that hippocampal BDNF mRNA levels were in both sublines similarly upregulated by fluoxetine treatment (p=0.0353 for the effect of treatment ; p=0.891 for TxS interaction), and were higher in high-5HT than low-5HT animals (p=0.0127 for the effect of the subline). Hippocampal BDNF protein levels were significantly affected by fluoxetine treatment in high-5HT (p<0.01), but no in low-5HT (p>0.05) animals (p=0.0092 for TxS interaction), and were basally higher in high-5HT than low-5HT animals (p=0.0059). Conclusion: Differences in fluoxetine- induced changes in hippocampal BDNF protein levels between hypo- and hyperserotonergic rats support interaction of 5HT and BDNF pathways in mediating fluoxetine action. However, the weight loss caused by fluoxetine treatment seems not to be related to endogenous 5HT activity of the animal.

serotonin ; BDNF ; Wistar-Zagreb 5HT rats ; fluoxetine ; body weight

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