CB-839 Experiment Blunted fear potentiated startle due to de
Experiment 2: Blunted fear-potentiated startle due to deficient fear acquisition. SERT+/+ and SERT+/− showed significant acquisition of the cue-shock association, whereas SERT−/− did not (trial×genotype interaction: F2,50=3.3, p<0.05; effect of trial: SERT+/+F1,17=10.1, p<0.01; SERT+/−F1,18=5.0, p<0.05; and SERT−/−F1,15<1, Figure 2A and C). In addition, whereas SERT+/+ differentiated between cued and non-cued trials during both the first and second phase of acquisition (1st phase [T1,17=−2.6, p<0.05], 2nd phase [T1,17=−3.0, p<0.01]), SERT+/− only differentiated between cued and non-cued trials during the first phase of acquisition (1st phase [T1.18=−2.9, p<0.001], 2nd phase T1,18=−1.7, NS]). The response to non-cued trials increased over time independently of genotype [phase×genotype interaction and overall effect phase on non-cued trials F4,106<1 and F2,106=36.6, p<0.001]. Experiment 3: Neither acute nor chronic pharmacological SERT inhibition affects the acquisition and CB-839 of fear-potentiated startle. Acquisition: Following fear acquisition significant FPS was induced (Effect of trial [F1,30=39.3, p<0.001] and [F1.32=32.0, p<0.001] in acute and chronic group respectively) and neither acute nor chronic paroxetine treatment significantly affected the level of fear acquisition, as measured 24h later ([drug×trial interaction F1,30<1 and F2,32<1 in acute and chronic group respectively]; Figure 3A and C). Rather, acute paroxetine treatment during acquisition increased overall startle responding 24h later [main effect dose F1,30=3.6, p<0.05], an effect that was primarily mediated by the 10mg/kg dose [p=0.053]. Expression: Neither acute nor chronic paroxetine treatment affected the expression of FPS in pre-trained rats (trial×dose interaction F2,30<1 for both time points; Figure 3B and D). Significant FPS was established at both time points measured (Effect of trial [F1,30=19.0, p<0.001] and [F1,30=21.6, p<0.001] for acute and chronic treatment respectively). Experiment 4A: SERT−/− rats show exacerbated contextual conditioned fear in the fear-potentiated startle paradigm. The level of contextual conditioned fear was measured during non-cued trials. Separate analyses of non-cued trials in cue-no-shock and cue-shock groups showed that the level of contextual conditioned fear differed between genotypes [condition×genotype interaction F2,66=5.1, p<0.01]. More specifically, SERT−/− and SERT+/− in the cue-shock group showed clear contextual conditioned fear, which was reflected in a significant increase in response to non-cued trials compared to the cue-no-shock group ([F1,21=12.9, p<0.01] and [F1,23=7.7, p<0.05] in SERT−/− and SERT+/− respectively, Figure 4B and C). SERT+/+ rats, on the other hand, did not show contextual conditioned fear ([F1,21=1.5, NS], Figure 4A). Direct comparison of the three genotypes in the cue-shock group showed that SERT−/− rats showed exacerbated contextual conditioned fear during non-cued trials compared to SERT+/+, whereas SERT+/− did not (effect of genotype [F2,33=10.5, p=0.001]; post-hoc analyses SERT−/− vs SERT+/+ [p=0.001], SERT+/− vs SERT+/+ [p=0.953]). Furthermore, overall analyses of the FPS response in all genotypes confirmed the previously found disturbance in FPS in SERT−/− rats [condition×genotype×trial interaction: F2,66=3.7, p<0.05]. Both SERT+/+ and SERT+/− in the cue-shock group showed a significant increase in response to cued trials relative to cue-no-shock group (trial×condition interaction [F2,12=8.0, p=0.01] and [F1,23=9.7, p<0.01] in SERT+/+ and SERT+/− respectively). These genotypes also clearly differentiated between cued and non-cued trials, reflecting normal FPS. On the other hand, SERT−/− rats in the cue-shock group showed an overall increase in startle reactivity relative to the cue-no-shock control group (trial×condition interaction [F1,21<1] and overall effect of condition [F1,21=13.5, p=0.001]). In addition, these SERT−/− in the cue-shock group did not differentiate between cued and non-cued trials.