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

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-HT 1A autoreceptors and post-synaptic 5-HT 1A heteroreceptors in fear conditioning is still unclear. Objective To determine the role of pre- and post-synaptic 5-HT 1A receptors in the acquisition and expression of cued and contextual conditioned fear. Methods We studied the acute effects of four 5-HT 1A receptor ligands in the fear-potentiated startle test. Male Wistar rats were injected with the 5-HT 1A receptors biased agonists F13714 (0–0.16 mg/kg, IP), which preferentially activates somatodendritic 5-HT 1A autoreceptors, or F15599 (0–0.16 mg/kg, IP), which preferentially activates cortical post-synaptic 5-HT 1A heteroreceptors, with the prototypical 5-HT 1A receptor agonist R(+)8-OH-DPAT (0–0.3 mg/kg, SC) or the 5-HT 1A 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-HT 1A autoreceptors reduces cued fear learning, whereas 5-HT 1A receptors seem not involved in contextual fear learning. Moreover, activation of somatodendritic 5-HT 1A autoreceptors may reduce cued and contextual fear expression, whereas we found no evidence for the involvement of cortical 5-HT 1A heteroreceptors in the expression of conditioned fear.