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

ABSTRACT: RATIONALE:Fear 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. OBJECTIVE:To determine the role of pre- and post-synaptic 5-HT1A receptors in the acquisition and expression of cued and contextual conditioned fear. METHODS:We 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). RESULTS:F13714 (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. CONCLUSIONS:The 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.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC6591185 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Activation of somatodendritic 5-HT<sub>1A</sub> autoreceptors reduces the acquisition and expression of cued fear in the rat fear-potentiated startle test.

Zhao Yulong Y Bijlsma Elisabeth Y EY Ter Heegde Freija F Verdouw Monika P MP Garssen J J Newman-Tancredi Adrian A Groenink Lucianne L

Psychopharmacology 20181212 4

<h4>Rationale</h4>Fear conditioning is an important factor in the etiology of anxiety disorders. Previous studies have demonstrated a role for serotonin (5-HT)<sub>1A</sub> receptors in fear conditioning. However, the relative contribution of somatodendritic 5-HT<sub>1A</sub> autoreceptors and post-synaptic 5-HT<sub>1A</sub> heteroreceptors in fear conditioning is still unclear.<h4>Objective</h4>To determine the role of pre- and post-synaptic 5-HT<sub>1A</sub> receptors in the acquisition and ex ...[more]

PMID: 30539269

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Project description:BackgroundMajor theories propose that perturbed threat learning is central to pathological anxiety, but empirical support is inconsistent. Failures to detect associations with anxiety may reflect limitations in quantifying conditioned responses to anticipated threat, and hinder translation of theory into empirical work. In prior work, we could not detect threat-specific anxiety effects on states of conditioned threat using psychophysiology in a large sample of patients and healthy comparisons. Here, we examine the utility of an alternative fear potentiated startle (FPS) scoring in revealing associations between anxiety and threat conditioning and extinction in this dataset. Secondary analyses further explored associations among conditioned threat responses, subcortical morphometry, and treatment outcomes.MethodsYouths and adults with anxiety disorders and healthy comparisons (n = 306; 178 female participants; 8-50 years) previously completed a well-validated differential threat learning paradigm. FPS and skin conductance response (SCR) quantified psychophysiological responses during threat conditioning and extinction. In this report, we examined normalizing raw FPS scores to intertrial intervals (ITI) to address challenges in more common approaches to FPS scoring which could mask group effects. Secondary analyses examined associations between FPS and subcortical morphometry and with response to exposure-based cognitive behavioral therapy in a subsample of patients.ResultsPatients and comparisons showed comparable differential threat conditioning using FPS and SCR. While SCR suggested comparable extinction between groups, FPS revealed stronger retention of threat contingency during extinction in individuals with anxiety disorders. Extinction indexed with FPS was not associated with age, morphometry, or anxiety treatment outcome.ConclusionITI-normalized FPS may have utility in detecting difficulties in extinguishing conditioned threat responses in anxiety. These findings provide support for extinction theories of anxiety and encourage continued research on aberrant extinction in pathological anxiety.

Dataset Information

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

Publications

Activation of somatodendritic 5-HT<sub>1A</sub> autoreceptors reduces the acquisition and expression of cued fear in the rat fear-potentiated startle test.

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