Behavioral and neurochemical effects of novel N-Benzyl-2-phenylethylamine derivatives in adult zebrafish
Konstantin A. Demin, Olga V. Kupriyanova, Вадим А. Шевырин, Ksenia A. Derzhavina, Nataliya A. Krotova, Nikita P. Ilyin, Tatiana O. Kolesnikova, David S. Galstyan, Iurii M. Kositsyn, Abubakar-Askhab S. Khaybaev, Maria Seredinskaya, Yaroslav A. Dubrovskii, Raziya G. Sadykova, Maria O. Nerush, Mikael S. Mor, Elena V. Petersen, Tatyana Strekalova, Evgeniya Efimova, Dmitrii V. Bozhko, Vladislav Myrov, Sofia M. Kolchanova, Aleksander I. Polovian, Georgii K. Galumov, Allan V. Kalueff
bioRxiv (Cold Spring Harbor Laboratory) January 21, 2022 preprint DOI: 10.1101/2022.01.19.476767 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Adult zebrafish (Danio rerio) |
| Interventions | 24H-NBF 24H-NBOMe 34H-NBF 34H-NBBr 34H-NBCl 34H-NBOMe 24H-NBBr 24H-NBCl 24H-NBOMe(F) 34H-NBOMe(F) |
| Topics | MDMA Mescaline Serotonin |
| Keywords | Neurochemical Hallucinogen Anxiogenic Phenethylamine Pharmacology Tryptamine Zebrafish Dopamine Anxiolytic Biochemistry Receptor |
| Key findings | Substitutions in the N-benzyl and phenethylamine moieties of NBPEA derivatives differentially affect zebrafish locomotion and anxiety-like behavior, with some compounds showing anxiolytic/hallucinogenic-like effects and potential clinical relevance. |
Abstract
Abstract Serotonergic hallucinogenic drugs potently affect human brain and behavior, and have recently emerged as potentially promising agents in psychopharmacotherapy. Complementing rodent studies, zebrafish ( Danio rerio ) is a powerful animal model for screening neuroactive drugs, including serotonergic agents. Here, we test ten different N-Benzyl-2-phenylethylamine (NBPEA) derivatives with the 2,4- and 3,4-dimethoxy substitutions in the phenethylamine moiety and the - OCH3, -OCF3, -F, -Cl and -Br substitutions in the ortho position of phenyl ring of N -benzyl fragment, assessing their behavioral and neurochemical effects in adult zebrafish. Overall, substitutions in N -benzyl fragment primarily affected zebrafish locomotion, and in phenethylamine moiety - anxiety-like behavior, also modulating brain serotonin and/or dopamine turnover. We also identified several behavioral clusters, including anxiogenic/hypolocomotor (24H-NBF, 24H-NBOMe and 34H-NBF), behaviorally inert (34H-NBBr, 34H-NBCl and 34H- NBOMe), anxiogenic/hallucinogenic-like (24H-NBBr, 24H-NBCl and 24H-NBOMe(F)), and anxiolytic/hallucinogenic-like (34H-NBOMe(F)) agents. The 24H-NBOMe(F) and 34H-NBOMe(F) also reduced despair-like behavior in zebrafish. The artificial intelligence-driven phenotyping supports association of multiple compounds with NMDA antagonists and/or MDMA, supporting their potential hallucinogenic-like properties, as well as other valuable psychoactive effects. In silico functional molecular activity modelling also supports existing of similarities between studied NBPEAs drugs, MDMA, and ketamine. Functional analysis implicates potential involvement of serotonin release stimulating activity, calcium channel (voltage-sensitive) activity, some serotonin receptors activity and variety of psychiatric and neurologic disorders treatments activities. Overall, we report potent neuroactive properties of several novel synthetic N -benzylphenylethylamines in an in vivo vertebrate model system (zebrafish), raising the possibility of their potential use in clinical practice.
Comparable studies
Other preclinical and animal studies on mescaline, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Brain mechanisms of hallucinogens and entactogens Humans and rats | 2001 | Review | |
| Effects of hallucinogenic agents mescaline and phencyclidine on zebrafish behavior and physiology Zebrafish (Danio rerio) | 2012 | Experimental study | |
| Lysergic Acid Diethylamide- and Mescaline-Induced Attenuation of the Effect of Punishment in the Rat Rats | 1976 | Experimental study | |
| Dihydrobenzofuran Analogues of Hallucinogens. 3. Models of 4-Substituted (2,5-Dimethoxyphenyl)alkylamine Derivatives with Rigidified Methoxy Groups Rats (trained to discriminate saline from LSD tartrate) and rat cortical and... | 1996 | In vivo drug discrimination assay and in vitro radioligand binding assay |
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and 40 more in the library