The impact of chronic fluoxetine on conditioned fear expression and hippocampal FGF2 in rats: Short- and long-term effects

Phenotypic differences in conditioned fear expression may be a marker of vulnerability to the development of anxiety disorders. Hippocampal FGF2 correlates negatively with conditioned fear expression, and antidepressants, the first-line pharmacological treatment for anxiety, increase hippocampal FGF2. In the present study, we assessed whether treatment with the selective serotonin reuptake inhibitor fluoxetine reduces conditioned fear expression in rats that naturally express lower (Low fear) or higher (High fear) levels of fear following a single-trial conditioning session. Experiment 1 demonstrated that phenotypic differences in fear expression were highly stable over a two-week interval. Experiment 2 demonstrated that two weeks of fluoxetine treatment (administered via drinking water) reduced conditioned fear expression in both Low and High fear rats. Experiment 3 demonstrated that two weeks of fluoxetine reduced conditioned fear expression even when treatment commenced two weeks after fear conditioning, but not when conditioned fear was assessed following a two-week drug-free washout period. Additionally, fluoxetine increased hippocampal FGF2 levels relative to vehicle-treated rats, but only when measured immediately after fluoxetine treatment, and not two weeks after treatment termination. Together, these results provide further indirect evidence that endogenous hippocampal FGF2 may mediate individual differences in conditioned fear expression. They also suggest that fluoxetine may be effective in reducing conditioned fear expression in both vulnerable and resilient populations when administered immediately, or sometime after, aversive experiences, but these effects do not persist once treatment is terminated.