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-HT2A) 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-HT2A receptor antagonists ritanserin and aripirazole, but not by the 5-HT1A + 5-HT1B receptor antagonist propranolol and the 5-HT3 receptor antagonist granisetron, indicating 5-HT2A-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.
Highlights
Serotonin syndrome is caused by the excessive activation of serotonin (5-hydroxytryptamine: 5-HT) receptors in the nervous system, and is characterized by autonomic hyperactivity, mental-status changes, and neuromuscular abnormalities including rhabdomyolysis [1, 2]
5-HT2A receptor antagonists prevented 25B-NBOMe-induced hypo-locomotion, death and muscle injury aripiprazole or ritanserin (*p = 0.023 and **p = 0.013, respectively) (Fig. 3b). These findings indicated that 5-HT2A receptor was involved in rhabdomyolysis induced by 25B-NBOMe
Expression of the 5-HT2A receptor in zebrafish skeletal muscle was confirmed by reverse transcription polymerase chain reaction (Fig. 3d)
Summary
Serotonin syndrome is caused by the excessive activation of serotonin (5-hydroxytryptamine: 5-HT) receptors in the nervous system, and is characterized by autonomic hyperactivity, mental-status changes, and neuromuscular abnormalities including rhabdomyolysis [1, 2]. A combination of serotonergic drugs (precursors) can induce serotonin receptor 2A (5-HT2A)-dependent hyperthermia [4]. NBOMe poisoning can cause various symptoms that are similar to serotonin syndrome, including tachycardia, hypertension, agitation, hallucinations, seizures, hyperpyrexia, and myoclonus [6]. Because 45% of the lethal cases of serotonin syndrome presented high serum levels of creatine kinase, rhabdomyolysis may be a predominant cause of Forensic Toxicol (2017) 35:369–375 death in NBOMe intoxication [7]. We reported a case of serotonin syndrome with lethal rhabdomyolysis after the ingestion of 2-(4-bromo-2,5-dimethoxyphenyl)-N(2-methoxybenzyl) ethanamine (25B-NBOMe), one of the most potent 5-HT2A agonists with a1-adrenoceptor agonist activity [8]. Because the patho-physiological mechanism underlying rhabdomyolysis associated with serotonin syndrome is largely unknown, we hypothesized that 25B-NBOMe will contribute to the study of the mechanism of 5-HT2A-dependent rhabdomyolysis
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