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In the rapidly growing field of psychedelic research, psilocybin (and active metabolite psilocin) has been proposed as a promising candidate in the search for novel treatments for neuropsychiatric disorders. Clinical trials have revealed that psilocybin has a large, rapid, and persistent effect in the improvement of symptoms of depression and anxiety. The safety profile is considered favourable, with low toxicity and good tolerance. Several preclinical studies have also been carried out to determine the long-term mechanism of action of this drug. In this sense, preclinical studies in naïve animals as well as in animal models of disease have shown somewhat discrepant results in conventional tests for assessment of depression- and anxiety-like phenotype in response to psilocybin, but overall suggest positive outcomes. Additionally, several valuable assays in rodent models have been developed over the years to elucidate the neurochemical correlates of serotonin 2A receptor (5HT2AR) activation in the brain, primary molecular target of psilocin. This review aims to provide a general overview of the current and most recent literature in the therapeutic potential of psilocybin through a description of clinical trials of psilocybin-assisted psychotherapy, and to showcase the scene in the up-to-date preclinical research. A detailed description of preclinical rodent models and experimental approaches that have been used to study the neurobiological and behavioural actions of psilocybin is provided, and potential therapeutic mechanisms of action are discussed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jorge Emilio Ortega reports financial support was provided by Government of Spain Ministry of Health. Jorge Emilio Ortega reports financial support was provided by Basque Government. Jose Javier Meana reports financial support was provided by Center for Biomedical Research in Mental Health Network. Jorge Emilio Ortega reports financial support was provided by Vital Foundation. Jose Javier Meana reports a relationship with Janssen-Cilag SAS that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

Activation of serotonin 5-HT 3 receptor (5HT3R) in the locus coeruleus (LC), the principal somatodendritic noradrenergic area, decreases LC firing activity and noradrenaline (NA) release in prefrontal cortex (PFC). Blockade of 5HT3R in coadministration with selective serotonin reuptake inhibitors (SSRIs) has been proposed as a potential strategy to accelerate the onset of action of SSRIs. Dual-probe microdialysis in rats was used to evaluate the involvement of 5HT3R in the in vivo effect exerted by the SSRI citalopram on NA release. Besides, forced swimming test (FST) was carried out in mice to evaluate the antidepressant-like effect of citalopram in combination with a 5HT3R antagonist (Y25130). Systemic administration of the 5HT3R agonist SR57227 (10 mg/kg i.p.) increased NA in LC (Emax = 200 ± 27%) and PFC (Emax = 133 ± 2%). The increase in PFC was enhanced in local presence into LC of Y25130 (50 μM) (Emax = 296 ± 41%) suggesting an inhibitory function on NA release exerted by the activation of 5HT3R located in somatodendritic areas. Citalopram administration (10 mg/kg i.p.) increased NA in LC (Emax = 185 ± 11%) and decreased it in PFC (Emax = -35 ± 7%). Intra-LC (50 μM) or systemic co-administration of Y25130 (10 mg/kg i.p.) with citalopram (10 mg/kg i.p.) switched NA release in the PFC from an inhibition to a stimulatory effect. In mice FST, systemic coadministration of citalopram (2.5 mg/kg i.p.) and Y25130 (10 mg/kg i.p.) potentiated the decrease of immobility time through the increase of both swimming and climbing behaviours. These results suggest that the addition of a 5HT3R antagonist to SSRIs could represent a feasible strategy to improve antidepressant response., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The preparation of a number of (bis)guanidine and (bis)2-aminoimidazoline derivatives as potential alpha 2-adrenoceptor antagonists for the treatment of depression is presented. Human brain tissue was used to measure their affinity toward the alpha 2-adrenoceptors in vitro. Compounds 6b, 8b, 9b, 10b, 15b, 17b, 18b, 20b, and 21b displayed a good affinity (pKi > 7) and were evaluated in in vitro functional [(35)S]GTPgammaS binding assays in human prefrontal cortex to determine their agonistic or antagonistic activity. Among these compounds, 17b and 20b showed the expected behavior for an antagonist and were subject to in vivo microdialysis experiments in rats. Significantly, these experiments confirmed the antagonistic properties of 17b and 20b, and therefore both compounds can be considered as potential antidepressants.

The efficient preparation and pharmacological characterization of different families of (bis)guanidine and (bis)2-aminoimidazoline derivatives ("twin" and "half" molecules) as potential alpha(2)-adrenoceptor antagonists for the treatment of depression is presented. The affinity toward the alpha(2)-adrenoceptor of all the compounds prepared was measured in vitro in human brain tissue. Additionally, the activity as agonist or antagonist of those compounds with a pK(i) larger than 7 was determined in functional [(35)S]GTPgammaS binding assays in human brain tissue. Finally, the activity of the most promising compounds was confirmed by means of in vivo microdialysis experiments in rats. Compounds 1, 2b, 3b, 12b, 13b, 17b, 18b, 22b, 25b, 26b, 28b, and 30 showed a good affinity toward the alpha(2)-ARs. In general, the 2-aminoimidazoline derivatives displayed higher affinities than their guanidine analogues. Finally and most importantly, compounds 18b and 26b showed antagonistic properties over alpha(2)-ARs not only in vitro [(35)S]GTPgammaS binding but also in vivo microdialysis experiments. Moreover, both compounds have shown to be able to cross the blood-brain barrier and, therefore, they can be considered as potential antidepressants.