- Antidepressants facilitate neuroplasticity by stimulating trophic factors. This study evaluated the effect of fluoxetine (FLX) treatment on insulin-like growth factor-1 (IGF-1) in the rat brain and its role in the effect of FLX on cognition. IGF-1 receptor (IGF-1R) protein expression and IGF-1 mRNA levels were assessed in rat frontal cortex (FC) and hippocampus, in FLX-treated [15 mg/kg, orally; 3 (acute) or 21 (repeated) days] male Wistar rats. Rats were subjected to the Morris Water Maze test. Acute FLX administration decreased IGF-1 mRNA levels in the FC and hippocampus and increased IGF-1R levels in the FC. Repeated FLX increased both mRNA and IGF-1R levels in the FC. Repeated, but not acute, FLX treatment decreased IGF-1 mRNA in the hippocampus. FLX did not affect cognitive performance. Thus, repeated FLX treatment leads to upregulation of IGF-1 system is FC. It is possible that FLX affect FC neuroplasticity through activation of the IGF-1 system.