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Effects of Anti-Depressants, Bessa & Santarelli

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            Santarelli et al reported two results: (1) fluoxetine induces hippocampal neurogenesis and reduces latency to feed in the NSF test via 5-HT1A receptors and (2) hippocampal irradiation halts neurogenesis in the subgranular zone (SGZ), causing fluoxetine to have no anti-depressant effect. Santarelli’s experiments were elegantly done, but I’m not convinced that neurogenesis is the cause of the effects seen from fluoxetine. Using 5HT1A-R knockout mice demonstrated that chronic treatment with fluoxetine is sufficient to reduce latency to feed in WT mice; however, the same effect is seen using 8-OH-DPAT, a 5HT1A-selective agonist. How do we know if the fluoxetine-induced neurogenesis and its anti-depressant effects are independent of each other or not? If fluoxetine and 8-OH-DPAT have the same effects, couldn’t the reduced latency to feed be caused solely by agonists binding 5HT1A receptors? Neurogenesis occurs, but there’s no timeline of when it happened relative to the decreased latency to feed occurred.
            Similar to their first results, Santarelli et al show data that the number of BrdU+ cells decrease following hippocampal irradiation, but they do not say if 5HT1A receptors are affected by the radiation, nor do they specify which strain of mice they irradiate. Therefore, isn’t it possible that the radiation is simply damaging 5HT1A receptors, which then prevents fluoxetine from working? If a method to quantify the amount of 5HT1A receptors exists, I would have liked to see these data in Santarelli’s experiment.
            Bessa et al reported data mainly in opposition to Santarelli. Namely, Bessa reported that neurogenesis was important for the behavioral effects seen from using anti-depressants, but not for the mechanism of the drug itself. Using MAM as a method of arresting neurogenesis is, in my opinion, a more reliable method than irradiation. Bessa’s data also imply that restoration of synaptic contacts was the possible mechanism by which anti-depressants were working. This raises the question: Before the administration of anti-depressants, could synaptic remodeling occur outside of the hippocampus and PFC to mediate depressive-like behaviors? Other pathways in the brain that are involved in stress and fear may be strengthened and weakened under stressful conditions or with anti-depressant treatments.
            The Santarelli and Bessa paper provide a good overview of the possible effects that symptoms of depression and anti-depressants may have on the brain. However, there is no definitive mechanism of depression or its treatment that has been identified, thus indicating the need for further research. New techniques such as DREADDS, optogenetics, or genetic knockouts of Ncam1 or Syn1 genes could provide more specific results about the function of the hippocampus and PFC in depression.  



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