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ABSTRACT Article: Effects of combined nicotine and fluoxetine treatment on adult hippocampal neurogenesis and conditioned place preference Corresponding author: Dr. Ramon O. Bernabeu Journal: Neuroscience Our reference: NSC16267 PII: S0306-4522(15)00449-2 DOI: 10.1016/j.neuroscience.2015.05.017 Neurogenesis that occurs in adult mammals within the dentate gyrus, a hippocampal subarea, is known to be increased by antidepressant treatment and reduced in response to nicotine administration. We report here that chronic, but not acute treatment with the antidepressant fluoxetine was able to abolish the decrease in adult dentate cell proliferation produced by nicotine treatment. By using the conditioned place preference (CPP) paradigm, we also gave both drugs in a context in which their rewarding properties could be measured. Fluoxetine, which by itself induced a less robust but significant CPP when compared to nicotine, reduced the nicotine-induced CPP in response to a single injection. Moreover, the rewarding properties of nicotine were completely abolished in response to chronic fluoxetine treatment. Molecular markers related to neurogenesis in the dentate gyrus were measured. Both drugs increased the expression of p75NTR (p75 nerve growth factor receptor), which is known to promote proliferation and early maturation of dentate gyrus cells. Expression of nicotine-induced CPP markers, such as phospho-CREB (cyclic AMP responsive element binding protein) or the histone deacetylase HDAC2, indicated that CREB activation in the NAc plays a major role during nicotine-induced CPP. The data suggest that fluoxetine reward, as opposed to nicotine reward, depends on dentate gyrus neurogenesis. In addition, chronic fluoxetine treatment not only antagonized the reducing effect of nicotine on neurogenesis, but it was also able to reduce nicotine-induced CPP. Keywords: Conditioned place preference, Fluoxetine, Histone deacetylase, Neurogenesis, Nicotine, Phospho-CREB