Fmoc-Thr(tBu)-OH mg Another important mediator in fear learn
Another important mediator in fear learning is the neuropeptide corticotropin-releasing factor (CRF). For example, local repeated administration of CRF into the basolateral amygdala potentiates the acquisition of cue-conditioned fear (Bijlsma et al., 2011) and CRF1 receptor antagonists effectively block the acquisition and expression of contextual conditioned fear (Hubbard et al., 2007, Walker et al., 2009).
Several studies suggest direct interactions between serotonin and CRF in the regulation of anxiety-like responses (Lukkes et al., 2009, Meloni et al., 2008). In addition, central administration of CRF decreases activity of serotonin neurons in the raphe and serotonin release in forebrain regions in a dose-dependent manner (Kirby et al., 2000, Price and Lucki, 2001). Interestingly, a recent study within our department showed that interactions between serotonin transporter and CRF1 receptor polymorphisms are associated with deficient associative fear learning in healthy subjects (Heitland et al., 2013). Together, these studies suggest that especially the interplay between these two Fmoc-Thr(tBu)-OH mg systems may be important for adequate fear learning.
This study aimed at further studying the role of the serotonin transporter in classical fear conditioning deficits using a SERT knockout (SERT−/−) model in rats. This SERT−/− rat was created by N-ethyl-N-nitrosurea (ENU)-driven target-selected mutagenesis resulting in a premature stop codon (Smits et al., 2006). This premature stop codon results in a complete ablation of SERT in the SERT−/− rat (Homberg et al., 2007a). This SERT−/− rat shows selective disturbances in 5-HT homeostasis, including nine-fold higher extracellular 5-HT levels in the hippocampus and decreased intracellular availability of 5-HT (Homberg et al., 2007a). Behaviorally, the SERT−/− rat shows increased anxiety-like behavior in exploration-driven paradigms (Olivier et al., 2008), decreased memory performance in an object recognition paradigm (Olivier et al., 2009), but improved inhibitory control (Homberg et al., 2007b). Here we studied classical fear conditioning in SERT−/− rats by measuring potentiation of the acoustic startle response (i.e. fear-potentiated startle), a robust measure of defensive states in both humans and rodents (Bijlsma et al., 2011, Grillon, 2008). Recently, it was reported that panic disorder patients show an associative fear learning deficit in this fear-potentiated startle paradigm, resulting fear-like responding to safety cues (Lissek et al., 2009). To differentiate between developmental and direct effects of reduced SERT functioning, the effect of pharmacological SERT inhibition in adulthood on the acquisition and expression of fear-potentiated startle were studied following acute and chronic paroxetine treatment in Wistar rats. In addition, because of above mentioned interactions between serotonin and CRF and the putative inhibitory effects of CRFR1 antagonists on contextual conditioned fear, we studied changes in CRF1 receptor levels in SERT−/− rats and tested the hypothesis that the CRFR1 antagonist CP154,526 was able to normalize the fear learning deficits found.
Results Experiment 1: SERT−/− rats show no fear-potentiated startle. With both shock intensities, genotypes differed in their response to cued and non-cued trials (trial×genotype interaction: [F2,42=4.9, p<0.05 and F2,52=8.9, p<0.001 for 0.3 and 0.6mA respectively]): SERT+/+ and SERT+/− showed significant potentiation of the startle response whereas SERT−/− did not (SERT+/+: F1,11=12.4, p<0.01, SERT+/−: F1,15=18.6, p=0.001, SERT−/−: F1,16=1.2, NS; Figure 1A and B). The response to non-cued trials was increased in SERT−/− following 0.6mA, but not 0.3mA FPS training. However, this effect did not reach significance (effect genotype on non-cued trials [F2,42<1] and [F2,52=2.8, p<0.1] for 0.3 and 0.6mA respectively). The blunted FPS response in SERT−/− under both shock intensities was also reflected in a significantly lower percentage FPS (Effect of genotype [F2,42=6.5, p<0.01] and [F2,52=4.4, p<0.05] for 0.3 and 0.6mA respectively, Figure 1C and D).