Abstract
A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n = 6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n = 6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [3H]UCB-J (SV2A), [3H]MDL100907 (5-HT2AR antagonist) and [3H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.42% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (−15.21% to −50.19%). These differences were statistically significant in the hippocampus for all radioligands and in the PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in the hippocampus (+9.24%) and the PFC (+6.10%), whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin causes increased persistent synaptogenesis and an acute decrease in 5-HT2AR density, which may play a role in psilocybin’s antidepressive effects.
Highlights
Introduction published maps and institutional affilSerotonergic psychedelic drugs have for centuries been extensively used in religious practices and recreationally [1]
Compared to the saline-treated group, psilocybin treatment was associated with 4.42% higher synaptic vesicle protein 2A (SV2A) in the hippocampus (p < 0.0001) one day after psilocybin injection and 9.24% higher SV2A in the hippocampus (p = 0.024) seven days after psilocybin (Figure 1a and Table 1)
To the best of our knowledge, this is the first large-animal study to investigate how a single dose of psilocybin changes the key proteins SV2A and 5-HT2A R in brain regions involved in emotional processing
Summary
Serotonergic psychedelic drugs have for centuries been extensively used in religious practices and recreationally [1]. Their neurobiological and behavioral effects in mammals are mediated through stimulation of the serotonin 2A receptor (5-HT2A R) as reviewed by Vollenweider et al [2,3]. Psychedelic stimulation of 5-HT2A R, a G-protein-coupled receptor (GPCR), has recently shown potential as an anxiolytic and antidepressant therapy. Some clinical studies suggest that a single dose of psilocybin rapidly and effectively relieves symptoms in depression and anxiety, with effects that persist long after the psychedelic experience [6,7,8,9]. Research in rodents suggests that psilocybin, lysergic acid diethylamide (LSD), 2,5-dimethoxy4-iodoamphetamine (DOI), N,N-dimethyltryptamine (DMT), and alkaloids like harmine, iations
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