A Complex Impact of Systemically Administered 5-HT(2A) Receptor Ligands on Conditioned Fear

BACKGROUND: Though drugs binding to serotonergic 5-HT(2A) receptors have long been claimed to influence human anxiety, it remains unclear if this receptor subtype is best described as anxiety promoting or anxiety dampening. Whereas conditioned fear expressed as freezing in rats is modified by application of 5-HT(2A)–acting drugs locally into different brain regions, reports on the effect of systemic administration of 5-HT(2A) receptor agonists and 5-HT(2A) antagonists or inverse agonists on this behavior remain sparse. METHODS: We assessed the possible impact of systemic administration of 5-HT(2A) receptor agonists, 5-HT(2A) receptor inverse agonists, and a selective serotonin reuptake inhibitor (SSRI)—per se or in combination—on the freezing displayed by male rats when re-exposed to a conditioning chamber in which they received foot shocks 7 days earlier. RESULTS: The 5-HT(2A) receptor agonists psilocybin and 25CN-NBOH induced a reduction in conditioned fear that was countered by pretreatment with 5-HT(2A) receptor inverse agonist MDL 100907. While both MDL 100907 and another 5-HT(2A) receptor inverse agonist, pimavanserin, failed to impact freezing per se, both compounds unmasked a robust fear-reducing effect of an SSRI, escitalopram, which by itself exerted no such effect. CONCLUSIONS: The results indicate that 5-HT(2A) receptor activation is not a prerequisite for normal conditioned freezing in rats but that this receptor subtype, when selectively over-activated prior to expression, exerts a marked fear-reducing influence. However, in the presence of an SSRI, the 5-HT(2A) receptor, on the contrary, appears to counter an anti-freezing effect of the enhanced extracellular serotonin levels following reuptake inhibition.