Activation of somatodendritic 5-HT1A autoreceptors reduces the acquisition and expression of cued fear in the rat fear-potentiated startle test

Monika P Verdouw,Elisabeth Y Bijlsma,J Garssen,Freija Ter Heegde,Lucianne Groenink,Adrian Newman-Tancredi,Yulong Zhao

doi:10.1007/s00213-018-5124-0

Monika P Verdouw, Elisabeth Y Bijlsma + Show 5 more

Open Access

https://doi.org/10.1007/s00213-018-5124-0

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Abstract

RationaleFear conditioning is an important factor in the etiology of anxiety disorders. Previous studies have demonstrated a role for serotonin (5-HT)1A receptors in fear conditioning. However, the relative contribution of somatodendritic 5-HT1A autoreceptors and post-synaptic 5-HT1A heteroreceptors in fear conditioning is still unclear.ObjectiveTo determine the role of pre- and post-synaptic 5-HT1A receptors in the acquisition and expression of cued and contextual conditioned fear.MethodsWe studied the acute effects of four 5-HT1A receptor ligands in the fear-potentiated startle test. Male Wistar rats were injected with the 5-HT1A receptors biased agonists F13714 (0–0.16 mg/kg, IP), which preferentially activates somatodendritic 5-HT1A autoreceptors, or F15599 (0–0.16 mg/kg, IP), which preferentially activates cortical post-synaptic 5-HT1A heteroreceptors, with the prototypical 5-HT1A receptor agonist R(+)8-OH-DPAT (0–0.3 mg/kg, SC) or the 5-HT1A receptor antagonist WAY100,635 (0–1.0 mg/kg, SC).ResultsF13714 (0.16 mg/kg) and R(+)-8-OH-DPAT (0.03 mg/kg) injected before training reduced cued fear acquisition. Pre-treatment with F15599 or WAY100,635 had no effect on fear learning. In the fear-potentiated startle test, F13714 (0.04–0.16 mg/kg) and R(+)-8-OH-DPAT (0.1–0.3 mg/kg) reduced the expression of cued and contextual fear, whereas F15599 had no effect. WAY100,635 (0.03–1.0 mg/kg) reduced the overall startle response.ConclusionsThe current findings indicate that activation of somatodendritic 5-HT1A autoreceptors reduces cued fear learning, whereas 5-HT1A receptors seem not involved in contextual fear learning. Moreover, activation of somatodendritic 5-HT1A autoreceptors may reduce cued and contextual fear expression, whereas we found no evidence for the involvement of cortical 5-HT1A heteroreceptors in the expression of conditioned fear.

Highlights

Fear conditioning is considered an important factor in the etiology of anxiety disorders (Tinoco-Gonzalez et al 2015)
Several fear conditioning processes, including acquisition and expression, have been implicated in the pathogenesis of anxiety disorders (Lissek et al 2008; Duits et al 2015; Careaga et al 2016; Jasnow et al 2017) The fear-potentiated startle test, which is based on classical fear conditioning, has proven a valuable tool to study mechanisms involved in the acquisition and expression of conditioned fear in both rats and humans (Davis 1986; Grillon 2008)
Further analyses showed that F13714 had no significant effect on the magnitude of the startle response to cued or non-cued trials per se, but percent fear potentiation was significantly lower in rats that had received treatment with 0.16 mg/kg F13714 before acquisition training

Summary

Introduction

Fear conditioning is considered an important factor in the etiology of anxiety disorders (Tinoco-Gonzalez et al 2015). Besides the discrete cue conditioning, the environment in which subjects are trained to associate cue with shock will come to elicit unpredictable threat (McNish et al 1997). This conditioned contextual fear, known as background anxiety, is associated with an increase in the non-cued startle response (Guscott et al 2000; Groenink et al 2008). The increase in the non-cued startle response in the presence of contextual cues has been shown to be sensitive to anxiolytic drugs in rats (Santos et al 2006; Almada et al 2009; Ayers et al 2011; Zhao et al 2018b) and human subjects (Baas et al 2002; Grillon et al 2006)

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