Progress in Neuro-Psychopharmacology & Biological Psychiatry最新文献

Psilocybin represents a novel therapeutic approach for individuals with major depressive disorder (MDD) who do not respond to conventional antidepressant treatment. Investigating the influence of psilocybin on the pathophysiological processes involved in MDD could enhance our neurobiological understanding of the presumed antidepressant action mechanism. This systematic review aims to summarize the results of human studies investigating changes in blood-based biomarkers of MDD to guide future research on potentially relevant analytes that could be monitored in clinical trials. A systematic search was performed in MEDLINE, Embase, and Web of Science to retrieve studies investigating changes in serum and plasma levels of neurotrophic, immunologic, neuroendocrine, and metabolic markers. Nine studies were included, describing findings on 15 biomarkers, exclusively in healthy participants. Studies consistently reported a decrease in interleukin-6, C-reactive protein, and eosinophils, and an increase in cortisol, prolactin, oxytocin, thyroid-stimulating hormone, adrenocorticotropic hormone, brain-derived neurotrophic factor, and free fatty acids following psilocybin administration. Less consistent effects were observed on interleukin-1β, interleukin-8, tumour necrosis factor-alpha, soluble urokinase plasminogen activator receptor, and growth hormone. The results are in line with preclinical studies and provide initial support from human studies that psilocybin potentially leads to beneficial effects on biomarkers of MDD. However, given the limited number of studies, findings should be approached with caution prior to replication. Further research should include larger samples, clinical populations, longer-term assessment, rigorous experimental designs, and account for the potential confounding of psychological stress related to the psychedelic experience.

Amphetamine (AMPH) abuse represents a major global public health issue, highlighting the urgent need for effective therapeutic interventions to manage addiction caused by this psychostimulant. This study aimed to assess the potential of m-trifluoromethyl-diphenyldiselenide [(m-CF₃-PhSe)₂] in preventing the addictive effects induced by AMPH through targeting dopamine metabolism proteins. (m-CF₃-PhSe)₂ is of interest due to its demonstrated efficacy in mitigating opioid abuse, establishing it as a promising candidate for addiction treatment research. Initially, in silico studies examined the affinity of AMPH and (m-CF₃-PhSe)₂ for dopamine 1, 2, and 3 receptors (D1R, D2R, D3R), and dopamine transporter (DAT). In our experimental design, male Wistar rats were divided into four groups: I) Control; II) (m-CF₃-PhSe)₂; III) AMPH; IV) (m-CF₃-PhSe)₂ + AMPH. Animals were administered (m-CF₃-PhSe)₂ (0.1 mg/kg, by gavage) or canola oil (vehicle) 30 min before AMPH (4.0 mg/kg, i.p.) administration. Drug administration occurred for 8 days in the conditioned place preference (CPP) paradigm. Twenty-four hours after the last CPP conditioning section, preference for the drug-compartment was assessed, with anxiety-related effects and working memory were evaluated using the Y-maze test. Finally, animals were euthanized for striatal dissection to quantify D1R, D2R, D3R, and DAT levels in western blot. In silico findings suggest that (m-CF₃-PhSe)₂ may prevent AMPH activation in DAT, interacting with Asp46 and Phe319, preventing possible addictive effects of AMPH in DAT. In vivo results showed that (m-CF₃-PhSe)₂ attenuated AMPH effects, reducing preference for the drug-compartment in CPP test. Furthermore, (m-CF₃-PhSe)₂ prevented AMPH-induced anxiogenic effects in the elevated plus maze (EPM) test, similarly to light/dark test. No differences in locomotion or working memory were observed among the experimental groups in the Y-maze test. Ex vivo western blot analyses of the entire striatum indicates that (m-CF₃-PhSe)₂ prevented the AMPH-induced increase in D1R levels and decrease in D2R and DAT levels, with no changes in D3R levels. Overall, our study suggests that (m-CF₃-PhSe)₂ may interact with DAT sites similarly to AMPH, reducing drug-compartment preference and anxiogenic behaviors while maintaining dopaminergic metabolism proteins in the striatum, a key region involved in the onset and perpetuation of addiction.

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.