Acute Systemic Fibroblast Growth Factor-2 Enhances Long-Term Extinction of Fear and Reduces Reinstatement in Rats

Abstract

Despite having made substantial advances in the treatment of anxiety disorders over the past few decades it appears that we have now reached a 'therapeutic impasse'. Further clinical progress requires a greater understanding of the neural mechanisms underlying fear inhibition. In this study, we examined, for the first time, the effects of fibroblast growth factor-2 (FGF2), a mitogen involved in the molecular cascade of memory, on extinction and relapse in rats. In all experiments, rats were first trained to fear a white noiseconditioned stimulus, and then had this learned fear extinguished the following day. Extinction is the process underlying exposure-based therapy in humans. Experiments 1 and 2 demonstrated that FGF2 facilitated the loss of learned fear (ie, extinction) when given either prior to or immediately after extinction but not when given 4 h after extinction. This suggests that FGF2 must be present during the consolidation of the extinction memory to have an effect. Experiment 3 further supported this interpretation by showing that short-term extinction must occur for FGF2 to facilitate long-term extinction, suggesting that FGF2 is facilitating the translation of memory from short-term to long-term storage. In experiment 4 rats given FGF2 immediately after extinction exhibited less shock-induced reinstatement, which is a model preparation of relapse, than did vehicle-treated rats. Together, these experiments demonstrate that FGF2 facilitates extinction and attenuates relapse. Thus, FGF2 may be a novel pharmacological adjunct to exposure therapy.

Fibroblast Growth Factor-2 Enhances Extinction and Reduces Renewal of Conditioned Fear

“…Yet, the results of Experiments 2 and 3 clearly show that FGF2-treated rats are less susceptible to renewal. This finding, while surprising in one regard, does fit with our previous demonstration that FGF2-treated rats were less susceptible to reinstatement of an extinguished fear response (Graham and Richardson, 2009b). That is, taken together, these results show that FGF2-treated rats are less susceptible to common forms of relapse.…”

“…Furthermore, recent research has demonstrated that chronic administration of FGF2 reduces anxiety and depressive-like behavior in rats (Perez et al, 2009;Turner et al, 2008). However, we are the first to propose its use as a novel pharmacological adjunct to exposure therapy (Graham and Richardson, 2009b). The present experiments, coupled with our previous findings, highlight at least two potential benefits to using FGF2 in this way.…”

“…The present experiments, coupled with our previous findings, highlight at least two potential benefits to using FGF2 in this way. First, Experiments 2 and 3 demonstrate that extinction combined with FGF2 is as effective as double the amount of extinction without FGF2 (also see Graham and Richardson, 2009b). As exposure therapy is time-consuming and requires extensive commitment from the patient, the finding that FGF2 produces equivalent results in half the amount of time suggests that it may improve the efficiency of exposure therapy, which may reduce treatment dropout rates.…”

“…Our previous experiments have demonstrated that FGF2 must be combined with at least 15 extinction trials to facilitate long-term extinction, and that FGF2 is not effective when combined with only five extinction trials (Graham and Richardson, 2009b). This demonstrates that FGF2 is modulating some aspect of the extinction process to facilitate long-term extinction.…”

“…Furthermore, FGF2 affects the molecular cascade involved in learning and memory (Graham and Richardson, 2009a), and therefore acute FGF2 should enhance extinction of learned fear. Indeed, we have recently demonstrated that FGF2 administration does enhance long-term extinction of learned fear in rats, and further, that FGF2-treated rats are less susceptible to reinstatement, even when control rats were given double the amount of extinction training to equate levels of fear after extinction (Graham and Richardson, 2009b).…”