Effects of a psychedelic 5-HT2A receptor agonist on anxiety-related behavior and fear processing in mice

Abstract

Psychedelic-assisted psychotherapy gained considerable interest as a novel treatment strategy for fear-related mental disorders. Promising clinical results have been obtained with 3,4-m methylenedioxyamphetamine (MDMA)-assisted psychotherapy in patients with post-traumatic stress disorder (PTSD) but the underlying mechanism remains poorly understood. The serotonin 2A (5-HT2A) receptor is a key target underlying the effects of psychedelics on emotional arousal but its role in fear processing remains controversial. Using the psychedelic 5-HT2A/5-HT2C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and 5-HT2A receptor knockout (KO) mice we investigated the effect of 5-HT2A receptor activation on emotional processing. We show that DOI administration did not impair performance in a spontaneous alternation task but reduced anxiety-like behavior in the elevated plus maze task. Moreover, we found that DOI did not block memory recall but diminished fear expression in a passive avoidance task. Similarly, we found that DOI reduced fear expression in an auditory fear conditioning paradigm, while it did not affect fear extinction learning in wild type (WT) mice. The effect of DOI on fear expression was abolished in 5-HT2A receptor KO mice. Administration of DOI induced a significant increase of c-Fos expression in specific amygdalar nuclei. Moreover, local infusion of the 5-HT2A receptor antagonist M100907 into the amygdala reversed the effect of systemic administration of DOI on fear expression while local administration of DOI into the amygdala was sufficient to suppress fear expression. Our data demonstrate that activation of 5-HT2A receptors in the amygdala suppresses fear expression, but provide no evidence for an effect on fear extinction.

Sex-Specific Effects of Psychedelic Drug Exposure on Central Amygdala Reactivity and Behavioral Responding

“…In the males, there was decreased reactivity between the vehicle and psilocin group from baseline to the 28day follow up (F Interaction (1,19) with a significant reduction in reactivity at the 28-day follow up in the psilocin group (Šidák's: p=0.04). There were also reductions in the AUC at the follow up recordings in the psilocin group compared to the vehicle control (F Interaction (2,38)=0.2113, p=0.81; F Treatment (1,19)=4.926, p=0.03; F Time (2,38)=0.7906, p=0.46; Fig. 3E-F).…”

“…The CeA has also been shown to be heavily implicated in anxiety, depression, and PTSD [29,[31][32][33][34][35][36]. Preclinical studies have shown that administration of the 5-HT2AR agonist psychedelic compounds LSD and 2,5dimethoxy-4-iodoamphetamine (DOI) both promote increases in Fos expression in the amygdala [37,38] and that systemic and local DOI administration in the amygdala promotes suppression of fear response [38].…”

Psychedelic-Induced Serotonin 2A Receptor Downregulation Does Not Predict Swim Stress Coping in Mice

“…Moreover, previous studies have shown that the effects of DOI (in a dose of up to 2 mg/kg) on head twitching and other behaviors are completely abolished in 5-HT 2A receptor knockout mice. Head twitch behavior was observed immediately after drug administration [ 15 , 94 , 95 ].…”

“…Control mice received 10 mL/kg of 5% V/V DMSO in sterile saline. The low (0.2 mg/kg) and high (2.0 mg/kg) doses were selected based on preliminary data and the previous literature [ 95 , 131 ]. Mice received drug injections on day 6 of the experiment, one day before a forced swim test procedure and brain tissue extraction ( Figure 1 A).…”

The common fatty acids have a pheromone-like effect, improving the emotion in mice

“…Changes in serotonin neurotransmission and the specific serotonin receptor abnormalities are associated with mood disorders and schizophrenia 36,95 .The expression of 5HT2A receptor in mPFC is related to anxiety and depression and dopamine release 96,97 . There has been evidence that individuals with major depressive disorder have lower levels of 5HT1A mRNA in hippocampus compared with healthy 98,99 In current study, MA or MP exposure significantly increased the expression of 5HT1A in hippocampus or the expression of 5HT2A in mPFC, accounting for relieving anxiety and improving sexual orientation and boldness.…”