The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals. 1 Unlike most substance use disorder (SUD) medications, anecdotal reports suggest that ibogaine possesses the potential to treat patients addicted to a variety of substances including opiates, alcohol, and psychostimulants. Like other psychedelic compounds, its therapeutic effects are long-lasting, 2 which has been attributed to its ability to modify addiction-related neural circuitry through activation of neurotrophic factor signaling. 3 , 4 However, several safety concerns have hindered the clinical development of ibogaine including its toxicity, hallucinogenic potential, and proclivity for inducing cardiac arrhythmias. Here, we apply the principles of function-oriented synthesis (FOS) to identify the key structural elements of its potential therapeutic pharmacophore, enabling us to engineer tabernanthalog (TBG)—a water soluble, non-hallucinogenic, non-toxic analog of ibogaine that can be prepared in a single step. TBG promoted structural neural plasticity, reduced alcohol- and heroin-seeking behavior, and produced antidepressant-like effects in rodents. This work demonstrates that through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant with therapeutic potential.

Thyroid hormones (THs) regulate neurodevelopment, thus TH disruption is widely posited as a mechanism of developmental neurotoxicity for diverse environmental chemicals. Zebrafish have been proposed as an alternative model for studying the role of TH in developmental neurotoxicity. To realize this goal, it is critical to characterize the normal ontogenetic expression profile of TH signaling molecules in the developing zebrafish and determine the sensitivity of these molecules to perturbations in TH levels. To address these gaps in the existing database, we characterized the transcriptional profiles of TH transporters, deiodinases (DIOs), receptors (TRs), nuclear coactivators (NCOAs), nuclear corepressors (NCORs), and retinoid X receptors (RXRs) in parallel with measurements of endogenous TH concentrations and tshβ mRNA expression throughout the first five days of zebrafish development. Transcripts encoding these TH signaling components were identified and observed to be upregulated around 48-72 h post fertilization (hpf) concurrent with the onset of larval production of T4. Exposure to exogenous T4 and T3 upregulated mct8, dio3-b, trα-a, trβ, and mbp-a levels, and downregulated expression of oatp1c1. Morpholino knockdown of TH transporter mct8 and treatment with 6-propyl-2-thiouracil (PTU) was used to reduce cellular uptake and production of TH, an effect that was associated with downregulation of dio3-b at 120 hpf. Collectively, these data confirm that larval zebrafish express orthologs of TH signaling molecules important in mammalian development and suggest that there may be species differences with respect to impacts of TH disruption on gene transcription.

To screen the tens of thousands of chemicals for which no toxicity data currently exists, it is necessary to move from in vivo rodent models to alternative models, such as zebrafish. Here, we used dechorionated Tropical 5D wild-type zebrafish embryos to screen a 91-compound library provided by the National Toxicology Program (NTP) for developmental toxicity. This library contained 86 unique chemicals that included negative controls, flame retardants, polycyclic aromatic hydrocarbons (PAHs), drugs, industrial chemicals, and pesticides. Fish were exposed to 5 concentrations of each chemical or an equal amount of vehicle (0.5% DMSO) in embryo medium from 6 h post-fertilization (hpf) to 5 days post-fertilization (dpf). Fish were examined daily for mortality and teratogenic effects and photomotor behavior was assessed at 4 and 5 dpf. Of the 5 negative control compounds in the library, none caused mortality/teratogenesis, but two altered behavior. Chemicals provided in duplicate produced similar outcomes. Overall, 13 compounds caused mortality/teratology but not behavioral abnormalities, 24 only affected behavior, and 18 altered both endpoints, with behavior affected at concentrations that did not cause mortality/teratology (55/86 hits). Of the compounds that affected behavior, 52% caused behavioral abnormalities at either 4 or 5 dpf. Compounds within the same functional group caused different behavioral abnormalities, while similar behavioral patterns were caused by compounds from different groups. Our data suggest that behavior is a sensitive endpoint for developmental toxicity screening that integrates multiple modes of toxic action and is influenced by the age of the larval fish at the time of testing.

A major goal of translational toxicology is to identify adverse chemical effects and determine whether they are conserved or divergent across experimental systems. Translational toxicology encompasses assessment of chemical toxicity across multiple life stages, determination of toxic mode of action, computational prediction modeling, and identification of interventions that protect or restore health after toxic chemical exposures. The zebrafish is increasingly used in translational toxicology because it combines the genetic and physiological advantages of mammalian models with the higher-throughput capabilities and genetic manipulability of invertebrate models. Here, we review the recent literature demonstrating the power of the zebrafish as a model for addressing all four activities of translational toxicology. Important data gaps and challenges associated with using zebrafish for translational toxicology are also discussed.

Chemical exposures have been implicated as environmental risk factors that interact with genetic susceptibilities to influence individual risk for complex neurodevelopmental disorders, including autism spectrum disorder, schizophrenia, attention deficit hyperactivity disorder and intellectual disabilities. Altered patterns of neuronal connectivity represent a convergent mechanism of pathogenesis for these and other neurodevelopmental disorders, and growing evidence suggests that chemicals can interfere with specific signaling pathways that regulate the development of neuronal connections. There is, therefore, a growing interest in developing screening platforms to identify chemicals that alter neuronal connectivity. Cell-cell, cell-matrix interactions and systemic influences are known to be important in defining neuronal connectivity in the developing brain, thus, a systems-based model offers significant advantages over cell-based models for screening chemicals for effects on neuronal connectivity. The embryonic zebrafish represents a vertebrate model amenable to higher throughput chemical screening that has proven useful in characterizing conserved mechanisms of neurodevelopment. Moreover, the zebrafish is readily amenable to gene editing to integrate genetic susceptibilities. Although use of the zebrafish model in toxicity testing has increased in recent years, the diverse tools available for imaging structural differences in the developing zebrafish brain have not been widely applied to studies of the influence of gene by environment interactions on neuronal connectivity in the developing zebrafish brain. Here, we discuss tools available for imaging of neuronal connectivity in the developing zebrafish, review what has been published in this regard, and suggest a path forward for applying this information to developmental neurotoxicity testing.