title: Unique and potent effects of acute ibogaine on zebrafish: the developing utility of novel aquatic models for hallucinogenic drug research.
abstract: An indole alkaloid, ibogaine is the principal psychoactive component of the iboga plant, used by indigenous peoples in West Africa for centuries. Modulating multiple neurotransmitter systems, the drug is a potent hallucinogen in humans, although its psychotropic effects remain poorly understood. Expanding the range of model species is an important strategy for translational neuroscience research. Here we exposed adult zebrafish (Danio rerio) to 10 and 20mg/L of ibogaine, testing them in the novel tank, light-dark box, open field, mirror stimulation, social preference and shoaling tests. In the novel tank test, the zebrafish natural diving response (geotaxis) was reversed by ibogaine, inducing initial top swimming followed by bottom dwelling. Ibogaine also attenuated the innate preference for dark environments (scototaxis) in the light-dark box test. While it did not exert overt locomotor or thigmotaxic responses in the open field test, the drug altered spatiotemporal exploration of novel environment, inducing clear preference of some areas over others. Ibogaine also promoted 'mirror' exploration in the mirror stimulation test, disrupted group cohesion in the shoaling test, and evoked strong coloration responses due to melanophore aggregation, but did not alter brain c-fos expression or whole-body cortisol levels. Overall, our results support the complex pharmacological profile of ibogaine and its high sensitivity in zebrafish models, dose-dependently affecting multiple behavioral domains. While future investigations in zebrafish may help elucidate the mechanisms underlying these unique behavioral effects, our study strongly supports the developing utility of aquatic models in hallucinogenic drug research. High sensitivity of three-dimensional phenotyping approaches applied here to behavioral effects of ibogaine in zebrafish provides further evidence of how 3D reconstructions of zebrafish swimming paths may be useful for high-throughput pharmacological screening.
authors.affiliation: Department of Pharmacology and Neuroscience Program, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA; Zebrafish Neuroscience Research Consortium (ZNRC), Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cachat
authors.affiliation: Department of Pharmacology and Neuroscience Program, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA; Zebrafish Neuroscience Research Consortium (ZNRC), Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Kyzar
authors.affiliation: Department of Pharmacology and Neuroscience Program, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Collins
authors.affiliation: Department of Pharmacology and Neuroscience Program, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Gaikwad
authors.affiliation: Department of Pharmacology and Neuroscience Program, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Green
authors.affiliation: Department of Pharmacology and Neuroscience Program, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Roth
authors.affiliation: Department of Pharmacology and Neuroscience Program, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Ounsi
authors.affiliation: Department of Pharmacology and Neuroscience Program, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Davis
authors.affiliation: Department of Pharmacology and Neuroscience Program, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Mimi
authors.initials: M
authors.lastname: Pham
authors.affiliation: Department of Pharmacology and Neuroscience Program, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Landsman
authors.affiliation: Department of Pharmacology and Neuroscience Program, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA; Zebrafish Neuroscience Research Consortium (ZNRC), Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Adam Michael
authors.initials: AM
authors.lastname: Stewart
authors.affiliation: Department of Pharmacology and Neuroscience Program, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA; Zebrafish Neuroscience Research Consortium (ZNRC), Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, USA; ZENEREI Institute, 309 Palmer Court, Slidell, LA 70458, USA. Electronic address: avkalueff@gmail.com.
authors.forename: Allan V
authors.initials: AV
authors.lastname: Kalueff
mesh_terms: D000374:Aggression / Q000187:drug effects / Q000523:psychology; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D015415:Biomarkers; D003116:Color; D003624:Darkness; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D006213:Hallucinogens / Q000494:pharmacology*; D006854:Hydrocortisone / Q000378:metabolism; D007050:Ibogaine / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects; D012919:Social Behavior; D013550:Swimming; D014741:Video Recording; D015027:Zebrafish / Q000502:physiology*
chemical_list: D015415:Biomarkers; D006213:Hallucinogens; D007050:Ibogaine; D006854:Hydrocortisone