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.2021 Sep 21;24(9):749-757.
doi: 10.1093/ijnp/pyab040.

A Complex Impact of Systemically Administered 5-HT2A Receptor Ligands on Conditioned Fear

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A Complex Impact of Systemically Administered 5-HT2A Receptor Ligands on Conditioned Fear

Sven Melker Hagsäter et al. Int J Neuropsychopharmacol..

Abstract

Background: Though drugs binding to serotonergic 5-HT2A 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-HT2A-acting drugs locally into different brain regions, reports on the effect of systemic administration of 5-HT2A receptor agonists and 5-HT2A antagonists or inverse agonists on this behavior remain sparse.

Methods: We assessed the possible impact of systemic administration of 5-HT2A receptor agonists, 5-HT2A 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-HT2A receptor agonists psilocybin and 25CN-NBOH induced a reduction in conditioned fear that was countered by pretreatment with 5-HT2A receptor inverse agonist MDL 100907. While both MDL 100907 and another 5-HT2A 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-HT2A 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-HT2A receptor, on the contrary, appears to counter an anti-freezing effect of the enhanced extracellular serotonin levels following reuptake inhibition.

Keywords: 5-HT2A receptor; MDL 100907; TCB-2; pimavanserin; psilocybin.

© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.

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Figures

Figure 1.
Figure 1.
Fear conditioning protocol and time of injections in the fear conditioning experiments (I–IV and VI–VIII). Doses in parentheses are given as mg/kg.
Figure 2.
Figure 2.
Effect of the 5-HT2A receptor inverse agonist MDL 100907 on conditioned freezing displayed as percentage of time. MDL 100907 was administered 30 minutes prior to testing. Number of animals per group = 12. Bars represent median time spent freezing ± interquartile range. a = P < .05 vs saline.
Figure 3.
Figure 3.
Effect of the selective serotonin reuptake inhibitor escitalopram and different pretreatments (MDL 100907, pimavanserin, and SB 242084) on conditioned freezing displayed as percentage of time. The dose of escitalopram (ESC) was 5 mg/kg in all 3 experiments. MDL 100907, pimavanserin, and SB 242084 were administered 40 minutes prior to testing; escitalopram was administered 30 minutes prior to testing. Bars represent medians ± interquartile range. (A) Number of animals per group = 10. a = P < .05 vs saline; b = P < .01 vs saline; c = P < .01 vs escitalopram; d = P < .05 vs MDL 100907. (B) Number of animals per group = 11–12. a = P < .001 vs saline; b = P < .01 vs escitalopram; c = P < .01 vs pimavanserin. (C) Number of animals per group = 12. There were no significant differences between groups.
Figure 4.
Figure 4.
Effect of the selective serotonin reuptake inhibitor escitalopram and the 5-HT2A receptor inverse agonist MDL 100907 on behavior in the elevated plus maze. Shown are percentage of total time spent on open arms (A) and number of entries onto open arms (B). The dose of escitalopram (ESC) was 5 mg/kg. MDL 100907 was administared 40 minutes prior to testing; escitalopram was administered 30 minutes prior to testing. Number of animals per group = 15. Bars represent medians ±interquartile range. a = P < .05 vs saline.
Figure 5.
Figure 5.
Effect of the the 5-HT2A receptor agonists 25CN-NBOH, TCB-2, and psilocybin with or without pretreatment with the 5-HT2A receptor inverse agonist MDL 100907 and the 5-HT2C receptor antagonist SB 242084 on conditioned freezing displayed as percentage of time. The doses of MDL 100907 (MDL) and SB 242084 (SB) were 1 mg/kg in all experiments. MDL 100907 (A and C), SB 242084 (B), and the combination of the two (B) were administered 40 minutes prior to testing; 25CN-NBOH (A), TCB-2 (A and B), and psilocybin (C) were administered 30 minutes prior to testing. Bars represent medians ± interquartile range. (A) Number of animals per group = 10. a = P < .05 vs saline; b = P < .01 vs saline; c = P < .001 vs 25CN-NBOH plus MDL 100907. (B) Number of animals per group = 7–9. a = P < .01 vs saline; b = P < .05 vs saline. (C) Number of animals per group = 12. a = P < .01 vs saline; b = P < .01 vs MDL 100907 plus psilocybin.
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