INSIGHTS INTO THE LETHAL TOXICITY OF SYNTHETIC PSYCHOACTIVE CATHINONES FROM STUDIES IN LARVAL ZEBRAFISH

Abstract Use of synthetic psychoactive cathinones (SPCs) has been increasing worldwide over the past two decades, although the true extent of SPC use and abuse is probably underestimated. SPCs have similar structures to amphetamines and mimic the stimulant and other effects of amphetamines depending on structural motifs that give them properties that are similar to methamphetamine (METH), methylenedioxymethamphetamine (MDMA), or cocaine. As over 400 SPCs are illicitly used, high throughput behavioral and toxicological approaches are being developed this diverse set of drugs. In a series of studies at the University of Toledo, we have studied a closely related series of MDMA-like synthetic cathinones in our first efforts to develop structure-activity relationships for lethal toxicity. A series of studies has shown amphetamine-like behavioral outcomes and lethal toxicity, including neural, hepatic, and cardiac toxicity, as well as potentiation of lethal toxicity by high ambient temperatures. The mechanisms underlying toxicity to these organs has been confirmed, and the molecular mechanisms explored in more detail, using in vitro models for toxicity in each of those organs, as well as comparisons to lethal toxicity in mouse models. These additional approaches have helped to establish the validity of the model for human drug overdose, as well as contributing to understanding of the underlying mechanisms (which are surprisingly poorly understood even for classical stimulant drugs). Overall, there is substantial evidence for abuse potential of these drugs, and lethal toxicity that is similar to amphetamines. This lethal toxicity clearly varies with structural motifs, and it is likely that in a manner similar to fentanyl and heroin, some SPCs may have much greater potential for overdose than the drugs that they are replacing. The validity of the zebrafish model for predicting the effects of SPCs is shown by its ability to replicate many findings from rodent studies, including the effects of high ambient temperature on amphetamine/SPC lethal toxicity. It must be remembered however that the goal of these studies is to model human drug overdose. A number of factors complicate interpretations of human drug overdose, including concomitant use of other drugs, particularly ethanol and nicotine. In our zebrafish model we have shown that ethanol, not surprisingly, exacerbates the lethal toxicity of MDMA and methylone (the β-ketone SPC analogue of MDMA). However, nicotine was found to be highly protective against the lethal toxicity of both drugs. Once understood, this surprising effect may provide an approach to treating stimulant drug overdose, which may affect not just acute lethality, but perhaps also long-term consequences of drug overdose in survivors and chronic drug users. This series of studies clearly shows that this model can now be used to examine the wide range of SPC drugs in use (>400), to determine structure activity relationships underlying SPC abuse liability and lethal toxicity, and to develop treatments for acute lethality as well as to prevent longer-term consequences of SPC overdose.