CGRP antagonist infused into the bed nucleus of the stria terminalis impairs the acquisition and expression of context but not discretely cued fear

Abstract

Calcitonin gene-related peptide (CGRP) infusions into the bed nucleus of the stria terminalis (BNST) evoke increases in startle amplitude and increases in anxiety-like behavior in the plus maze. Conversely, intra-BNST infusions of the CGRP antagonist CGRP 8 -37 block unconditioned startle increases produced by fox odor. Here we evaluate the contribution of CGRP signaling in the BNST to the development and expression of learned fear. Rats received five pairings of a 3.7-sec light and footshock and were tested for fear-potentiated startle one or more days later. Neither pre-training (Experiment 1) nor pre-test (Experiment 2) infusions of the CGRP antagonist CGRP 8 -37 (800 ng/BNST) disrupted fear-potentiated startle to the 3.7-sec visual cue. However, in both experiments, CGRP 8 -37 infusions disrupted baseline startle increases that occurred when rats were tested in the same context as that in which they previously received footshock (Experiment 3). Intra-BNST CGRP 8 -37 infusions did not disrupt shock-evoked corticosterone release (Experiment 4). These data confirm previous findings implicating BNST CGRP receptors in fear and anxiety. They extend those results by showing an important contribution to learned fear and, specifically, to fear evoked by a shock-associated context rather than a discrete cue. This pattern is consistent with previous models of BNST function that have posited a preferential role in sustained anxiety as opposed to phasic fear responses. More generally, the results add to a growing body of evidence indicating behaviorally, possibly clinically, relevant modulation of BNST function by neuroactive peptides.

Nausea in the peri-traumatic period is associated with prospective risk for PTSD symptom development

“…The actions of calcitonin gene-related peptide (CGRP) in the parabrachial nucleus are necessary for activating the noradrenergic sympathetic system [34] and for a normal CTA response [35]. CGRP itself contributes to fear learning during fear conditioning in rodent models, and antagonism of CGRP impairs the acquisition of contextual fear [36]. While these data suggest that CGRP signaling in the immediate aftermath of trauma may be a future target to investigate for determining the mechanisms by which nausea increases risk for PTSD development, it is important to note that isolating nausea from experiences of threat and fear response activation in the context of trauma exposure is difficult.…”

Role of the bed nucleus of the stria terminalis in the acquisition of contextual fear at long or short context-shock intervals.

“…(Resstel et al, 2008; Sink et al, 2013; Zimmerman & Maren, 2011)). The sham and lesioned 1-min groups did not differ either during the conditioning trials or during the final test trial.…”

Extending the amygdala in theories of threat processing

“…For example, BST lesions attenuate motivated actions during long (10min) but not short (1min) threat-cue exposure [49]. Moreover, pharmacological activation of BST using Calcitonin gene-related peptide (CGRP) increases unconditioned responses during exposure to potentially threatening contexts that require sustained vigilance [50,51]. Another study demonstrated that Ce lesions decreased freezing to an aversively conditioned cue, whereas BST lesions blocked the increased baseline freezing occurring after repeated threat-cue presentation [52].…”