The psychoactive drug 25B-NBOMe recapitulates rhabdomyolysis in zebrafish larvae

Summary

25B-NBOMe, a potent designer drug that activates the serotonin-2A receptor, can cause lethal rhabdomyolysis—a severe breakdown of skeletal muscle—in zebrafish larvae. Treatment with 25B-NBOMe reduced survival, impaired movement, and disrupted muscle structure, as shown by changes in birefringence and immunostaining for dystroglycan and myosin heavy chain. This rhabdomyolysis was blocked by the 5-HT_2A receptor antagonists ritanserin and aripiprazole, but not by antagonists for other serotonin receptors, indicating a 5-HT_2A-dependent mechanism. The 25B-NBOMe-treated zebrafish provides a useful animal model for studying rhabdomyolysis and screening potential therapies.

Study at a glance

Abstract

N -Benzyl-substituted 2C class phenethylamines (NBOMes) are psychoactive designer drugs, with strong hallucinogenic and stimulant effects, even at low doses. The designer drug, 2-(4-bromo-2, 5-dimethoxyphenyl)- N -(2-methoxybenzyl) ethanamine (25B-NBOMe) is considered to be one of the most potent agonists of the serotonin-2A (5-HT_2A) receptor. Recently, we reported the first lethal case of 25B-NBOMe intoxication with severe rhabdomyolysis, concluded by clinical, pathological and toxicological analyses. There are currently no good animal models that closely recapitulate serotonin receptor-dependent rhabdomyolysis. In the present study, we created animal models of rhabdomyolysis using zebrafish larvae to study the pathomechanism of rhabdomyolysis, and demonstrated that 25B-NBOMe can simulate lethal rhabdomyolysis in this animal. Treatment of the larvae with 25B-NBOMe decreased their survival rate, locomotion, altered birefringence of the skeletal muscle and immunostainings for dystroglycan (a myoseptal protein) and myosin heavy chain (a myofibril protein), which were consistent with rhabdomyolysis. This 25B-NBOMe-induced rhabdomyolysis was inhibited by the 5-HT_2A receptor antagonists ritanserin and aripirazole, but not by the 5-HT_1A + 5-HT_1B receptor antagonist propranolol and the 5-HT_3 receptor antagonist granisetron, indicating 5-HT_2A-dependent rhabdomyolysis. The 25B-NBOMe-treated zebrafish is, therefore, a highly useful model of rhabdomyolysis for studying the pathomechanism of rhabdomyolysis as well as for therapeutic drug screening.