Fibroblast growth factor-2 enhances extinction and reduces renewal of conditioned fear

Abstract

Anxiety disorders are increasingly prevalent in society; hence, there is a need to improve on existing treatments for such disorders. Fibroblast growth factor-2 (FGF2), a mitogen that is involved in brain development and regeneration, has been shown to both facilitate long-term extinction of fear and reduce stress-precipitated relapse in rats. Extinction is the laboratory analog of exposure-based therapies in humans. In this study, we continued to investigate the clinical potential of FGF2 as a pharmacological enhancer of extinction by examining its effect on renewal, a common type of relapse. In all experiments, rats were trained to fear a white noise-conditioned stimulus, and then this learned fear was extinguished the following day. Rats received systemic injections of FGF2 or vehicle immediately after extinction training. At test, on the day after extinction training, levels of freezing elicited by the white noise in either the extinction context or the original training context were measured. FGF2-treated rats showed less renewal of fear when tested in the original training context than did vehicle-treated rats. This pattern occurred even when vehicle rats were given double the amount of extinction training, and when FGF2-treated rats were given equivalent exposure to the extinction context. These results show that FGF2 facilitates long-term extinction and attenuates relapse, and thus highlight its potential as a novel pharmacological adjunct to exposure therapy.

Figure 1

(a) Mean (±SEM) freezing by rats in response to the CS during extinction training in Experiment 1. (b) Mean (±SEM) CS-elicited freezing by rats during test in Experiment 1. Rats had been injected with vehicle (n=12), or 5 (n=12), 10 (n=13), or 20 (n=12) ng/g body weight FGF2 after extinction training.

Figure 2

(a) Mean (±SEM) CS-elicited freezing by vehicle- and FGF2-treated rats in response to the CS during extinction training in Experiment 2. Some of these rats were subsequently tested in the same context (vehicle-treated: n=12; FGF2-treated: n=11) whereas others were tested in a different context (vehicle-treated: n=13, FGF2-treated: n=12). Vehicle-treated rats received an additional 15 extinction trials during extinction training compared with FGF2-treated rats (data not shown). (b) Mean (±SEM) freezing by rats in response to the CS during test in Experiment 2.

Figure 3

(a) Mean (±SEM) CS-elicited freezing by vehicle- and FGF2-treated rats in response to the CS during extinction training in Experiment 3. Some of these rats were subsequently tested in the same context (vehicle-treated: n=8; FGF2-treated: n=8), whereas others were tested in a different context (vehicle-treated: n=8, FGF2-treated: n=7). Vehicle-treated rats received an additional 15 extinction trials during extinction training compared with FGF2-treated rats (data not shown). (b) Mean (±SEM) freezing by rats in response to the CS during test in Experiment 3.