by Keyword: anxiety

Madrid-Gambin F, Gomez-Gomez A, Busquets-Garcia A, Haro N, Marco S, Mason NL, Reckweg JT, Mallaroni P, Kloft L, van Oorsouw K, Toennes SW, de la Torre R, Ramaekers JG, Pozo OJ, (2022). Metabolomics and integrated network analysis reveal roles of endocannabinoids and large neutral amino acid balance in the ayahuasca experience Biomedicine & Pharmacotherapy 149, 112845

There has been a renewed interest in the potential use of psychedelics for the treatment of psychiatric conditions. Nevertheless, little is known about the mechanism of action and molecular pathways influenced by ayahuasca use in humans. Therefore, for the first time, our study aims to investigate the human metabolomics signature after consumption of a psychedelic, ayahuasca, and its connection with both the psychedelic-induced subjective effects and the plasma concentrations of ayahuasca alkaloids. Plasma samples of 23 individuals were collected both before and after ayahuasca consumption. Samples were analysed through targeted metabolomics and further integrated with subjective ratings of the ayahuasca experience (i.e., using the 5-Dimension Altered States of Consciousness Rating Scale [ASC]), and plasma ayahuasca-alkaloids using integrated network analysis. Metabolic pathways enrichment analysis using diffusion algorithms for specific KEGG modules was performed on the metabolic output. Compared to baseline, the consumption of ayahuasca increased N-acyl-ethanolamine endocannabinoids, decreased 2-acyl-glycerol endocannabinoids, and altered several large-neutral amino acids (LNAAs). Integrated network results indicated that most of the LNAAs were inversely associated with 9 out of the 11 subscales of the ASC, except for tryptophan which was positively associated. Several endocannabinoids and hexosylceramides were directly associated with the ayahuasca alkaloids. Enrichment analysis confirmed dysregulation in several pathways involved in neurotransmission such as serotonin and dopamine synthesis. In conclusion, a crosstalk between the circulating LNAAs and the subjective effects is suggested, which is independent of the alkaloid concentrations and provides insights into the specific metabolic fingerprint and mechanism of action underlying ayahuasca experiences. © 2022 The Authors

JTD Keywords: anxiety, dimethyltryptamine, integrative network analysis, metabolism, metabolomics, psychedelics, rats, subjective effects, system, tryptophan, Ayahuasca, Dimethyltryptamine, Integrative network analysis, Metabolomics, Psychedelics, Serotonin 5-ht2a, Subjective effects

Matamoros-Angles, A, Hervera, A, Soriano, J, Marti, E, Carulla, P, Llorens, F, Nuvolone, M, Aguzzi, A, Ferrer, I, Gruart, A, Delgado-Garcia, JM, Del Rio, JA, (2022). Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability Bmc Biology 20, 17

Background Cellular prion protein (PrP(C)) is a cell surface GPI-anchored protein, usually known for its role in the pathogenesis of human and animal prionopathies. However, increasing knowledge about the participation of PrP(C) in prion pathogenesis contrasts with puzzling data regarding its natural physiological role. PrP(C) is expressed in a number of tissues, including at high levels in the nervous system, especially in neurons and glial cells, and while previous studies have established a neuroprotective role, conflicting evidence for a synaptic function has revealed both reduced and enhanced long-term potentiation, and variable observations on memory, learning, and behavior. Such evidence has been confounded by the absence of an appropriate knock-out mouse model to dissect the biological relevance of PrP(C), with some functions recently shown to be misattributed to PrP(C) due to the presence of genetic artifacts in mouse models. Here we elucidate the role of PrP(C) in the hippocampal circuitry and its related functions, such as learning and memory, using a recently available strictly co-isogenic Prnp(0/0) mouse model (Prnp(ZH3/ZH3)). Results We performed behavioral and operant conditioning tests to evaluate memory and learning capabilities, with results showing decreased motility, impaired operant conditioning learning, and anxiety-related behavior in Prnp(ZH3/ZH3) animals. We also carried in vivo electrophysiological recordings on CA3-CA1 synapses in living behaving mice and monitored spontaneous neuronal firing and network formation in primary neuronal cultures of Prnp(ZH3/ZH3) vs wildtype mice. PrP(C) absence enhanced susceptibility to high-intensity stimulations and kainate-induced seizures. However, long-term potentiation (LTP) was not enhanced in the Prnp(ZH3/ZH3) hippocampus. In addition, we observed a delay in neuronal maturation and network formation in Prnp(ZH3/ZH3) cultures. Conclusion Our results demonstrate that PrP(C) promotes neuronal network formation and connectivity. PrP(C) mediates synaptic function and protects the synapse from excitotoxic insults. Its deletion may underlie an epileptogenic-susceptible brain that fails to perform highly cognitive-demanding tasks such as associative learning and anxiety-like behaviors.

JTD Keywords: anxiety, behavior, cellular prion protein, epilepsy, hippocampus, Anxiety, Behavior, Cellular prion protein, Developmental expression, Epilepsy, Gene-expression, Hippocampus, Kainate-induced seizures, Lacking, Ltp, Memory, Messenger-rna, Motor behavior, Mouse, Prp