Trends in Pharmacological Sciences
September 22, 2017
Evan J. Kyzar, Charles D. Nichols, Raul R. Gainetdinov et al.
155 citations
Psychedelic drugs like LSD, mescaline, and psilocybin produce strong effects on the brain and behavior. After decades of research difficulties, they are being tested again as possible treatments for hard-to-treat medical conditions. Preclinical research, human brain imaging, and early clinical trials suggest these compounds may help with addiction, depression, anxiety, and other disorders. However, many questions about how they work, their safety, and their effectiveness remain. This review summarizes recent preclinical and clinical data, discusses their pharmacological mechanisms, and outlines key areas for future research to maximize the potential benefits of psychedelic medicine for patients.
Progress in Neuro-psychopharmacology and Biological Psychiatry
January 10, 2012
Evan J. Kyzar, Christopher Collins, Siddharth Gaikwad et al.
122 citations
Mescaline and phencyclidine (PCP) dose-dependently increased top activity in the novel tank test, reduced immobility, and disrupted swimming patterns in zebrafish. PCP, but not mescaline, evoked circling behavior in the open field test. At the highest doses tested, mescaline markedly increased shoaling behavior, while PCP did not affect it. Whole-body cortisol levels were unchanged by 20 mg/l mescaline but elevated by 3 mg/l PCP. These findings indicate that zebrafish models are sensitive to hallucinogenic compounds, producing complex behavioral and physiological effects.
Behavioural Brain Research
January 1, 2013
Jonathan Cachat, Evan J. Kyzar, Christopher Collins et al.
112 citations
Ibogaine, a psychoactive compound from the iboga plant, alters multiple behaviors in adult zebrafish. At doses of 10 and 20 mg/L, it reversed the natural diving response, causing initial top swimming followed by bottom dwelling, and reduced the innate preference for dark environments. It did not change overall locomotion or wall-hugging behavior but altered spatial exploration, promoted mirror interaction, disrupted group cohesion, and induced color changes from melanophore aggregation. Brain c-fos expression and whole-body cortisol levels remained unchanged. These results demonstrate ibogaine's complex pharmacological profile and support the use of zebrafish for studying hallucinogenic drug effects.
Behavioural Pharmacology
April 8, 2011
Adam Stewart, Russell Riehl, Keith Wong et al.
66 citations
Acute exposure to high doses of MDMA (40-120 mg/l) reduces bottom swimming and immobility in zebrafish and impairs intrasession habituation at doses as low as 10 mg/l, while lower doses (0.25-10 mg/l) show no behavioral effects. MDMA also increases brain c-fos expression. These findings support the use of zebrafish as a model for screening hallucinogenic compounds.
ACS Chemical Neuroscience
September 25, 2018
Andrey D. Volgin, Oleg A. Yakovlev, Konstantin A. Demin et al.
38 citations
Deliriant hallucinogens, such as atropine and scopolamine, are a distinct class of drugs that induce hyperactivity and dream-like hallucinations by blocking muscarinic acetylcholine receptors. Despite their long history of use and being well-studied in cholinergic physiology, they are the least-studied class of hallucinogens regarding their behavioral and neurological effects. This review comprehensively evaluates the preclinical effects of these drugs in various animal models, detailing their mechanisms of action and potential interactions with other signaling pathways. It parallels experimental and clinical findings to outline future directions for translational research, emphasizing the need for novel approaches and new model organisms to investigate their central nervous system effects.
Zebrafish
March 22, 2016
Evan J. Kyzar, Allan V. Kalueff
29 citations
Interest in using hallucinogens to treat brain disorders is reviving. Early studies show classic serotonergic hallucinogens like LSD and psilocybin may help with addiction, PTSD, and anxiety, but basic pharmacological and toxicological questions remain. This paper discusses psychedelic medicine and the behavioral and toxic effects of hallucinogenic drugs in zebrafish, highlighting the fish as a model for screening both toxic and therapeutic effects of known and novel hallucinogenic compounds. Well-designed zebrafish studies could support the reemerging treatment paradigm of psychedelic medicine and open new clinical avenues for psychiatric disorders.
Behavioural Brain Research
July 14, 2017
Allan V. Kalueff, Aleksandra Kaluyeva, Émeline L. Maillet
21 citations
Noribogaine, the main psychoactive metabolite of ibogaine, produces robust anxiolytic-like behavior in adult zebrafish without affecting locomotion. In a 5-minute novel tank test following acute 20-minute immersion in 1, 5, or 10 mg/L noribogaine, treated fish spent more time and made more transitions to the top half compartment and showed fewer freezing bouts compared to controls. These results indicate noribogaine modulates components of the acute stress response related to emotionality and anxiety, suggesting it may be a potentially useful non-sedative anxiolytic agent.
ACS Chemical Neuroscience
June 7, 2022
Konstantin A. Demin, Olga V. Kupriyanova, Вадим А. Шевырин et al.
20 citations
Novel N-benzyl-2-phenylethylamine (NBPEA) derivatives, with specific substitutions in the N-benzyl and phenethylamine moieties, alter locomotion and anxiety-like behavior in adult zebrafish. Substitutions in the N-benzyl moiety modulate locomotion, while those in the phenethylamine moiety affect anxiety-like behavior and brain serotonin or dopamine turnover. The 24H–NBOMe(F) and 34H–NBOMe(F) treatments reduced despair-like behavior. Computational analyses classified the agents into anxiogenic/hypolocomotor, behaviorally inert, anxiogenic/hallucinogenic-like, and anxiolytic/hallucinogenic-like clusters, with some NBPEAs showing behavioral similarity to conventional serotonergic and antiglutamatergic hallucinogens. These findings suggest potent neuroactive properties of several NBPEAs, indicating potential clinical use or abuse.
Pharmacology, biochemistry, and behavior
December 1, 2024
Camilla W Pretzel, João V Borba, Cássio M Resmim et al.
5 citations
Acute exposure to subanesthetic doses of ketamine (20 and 40 mg/L) increased total distance traveled in adult zebrafish, indicating hyperlocomotion. All tested concentrations (2, 20, and 40 mg/L) elicited circling behavior, a stereotyped-like response that diminished over time. Ketamine also reduced thigmotaxis and homebase activity while increasing the average length of trips, suggesting anxiolytic-like effects on spatio-temporal exploratory dynamics. These findings support ketamine's modulatory influence on behavior and highlight homebase-related measurements as useful for assessing behavioral changes in zebrafish models.
The FASEB Journal
April 1, 2012
Evan J. Kyzar, Christopher Collins, Jeremy Green et al.
1 citation
Mescaline and phencyclidine (PCP) alter zebrafish behavior in distinct ways, while psilocybin shows no behavioral effects at the doses tested. Mescaline (10–20 mg/L) reduces anxiety-like behavior in the novel tank test, increases shoaling, and changes movement in the open field. PCP (1–3 mg/L) decreases freezing and causes erratic swimming. Both mescaline and PCP disrupt normal exploratory behavior. Psilocybin (0.5–3 mg/L) is inactive in all behavioral tests. Psilocybin and PCP raise whole-body cortisol levels without affecting brain c-fos expression; mescaline does not alter either measure. Zebrafish models are sensitive to hallucinogenic compounds with complex behavioral and physiological effects.
bioRxiv (Cold Spring Harbor Laboratory)
January 21, 2022
Konstantin A. Demin, Olga V. Kupriyanova, Вадим А. Шевырин et al.
preprint
Certain synthetic N-Benzyl-2-phenylethylamine (NBPEA) derivatives, related to hallucinogens like mescaline and MDMA, produce distinct behavioral and neurochemical effects in adult zebrafish. Substitutions on the N-benzyl fragment primarily affected locomotion, while those on the phenethylamine moiety influenced anxiety-like behavior. The compounds also modulated brain serotonin and/or dopamine turnover. Several behavioral clusters emerged: anxiogenic/hypolocomotor, behaviorally inert, anxiogenic/hallucinogenic-like, and anxiolytic/hallucinogenic-like. Two compounds reduced despair-like behavior. Artificial intelligence-driven phenotyping linked multiple compounds to NMDA antagonists and/or MDMA, suggesting hallucinogenic-like properties. In silico modeling indicated similarities between these NBPEAs, MDMA, and ketamine, implicating serotonin release, calcium channel activity, and serotonin receptor involvement.
Neurotoxicology and Teratology
January 1, 2017
Tatiana O. Kolesnikova, Sergey L Khatsko, Vadim A Shevyrin et al.
Tiletamine, a veterinary anesthetic related to ketamine, produces dose-dependent sedative effects in adult zebrafish. Immersion in 1 mg/L caused only reduced top entries in a novel tank test, while 5 and 10 mg/L caused robust sedation and skin darkening. Brain samples confirmed tiletamine presence only at the two higher doses. The results demonstrate potent neurotropic effects of tiletamine in zebrafish and support the use of fish-based aquatic screens for studying NMDA receptor antagonists.
Behavioural Brain Research
January 1, 2016
Evan J. Kyzar, Adam Michael Stewart, Allan V. Kalueff
The serotonin transporter (SERT) regulates serotonin signaling and is linked to psychiatric disorders like anxiety, autism spectrum disorders (ASD), and obsessive-compulsive disorder (OCD). In mice, removing the Sert gene increases anxiety and grooming behavior. This study examined the effects of the hallucinogen LSD (0.32 mg/kg) on grooming and other behaviors in mice with one copy of the Sert gene (Sert+/-). These mice showed longer self-grooming regardless of LSD treatment. LSD increased serotonin-sensitive behaviors like head twitching and tremors in both normal and Sert+/- mice, with no significant interaction between LSD and Sert gene dosage. The results suggest Sert+/- mice respond to LSD similarly to normal mice.