Antagonists for serotonin receptors ameliorate rhabdomyolysis induced by 25D-NBOMe, a psychoactive designer drug

Abstract

N-Benzyl-substituted phenethylamines (NBOMes) are psychoactive drugs, which induce various symptoms like serotonin syndrome, even at low doses. Recently, we reported the first lethal case of a designer drug, 2-(4-bromo-2, 5-dimethoxyphenyl)-NBOMe (25B-NBOMe) intoxication with severe rhabdomyolysis, evaluated by clinical, pathological, and toxicological analyses. We also confirmed that 25B-NBOMe can induce rhabdomyolysis using a zebrafish model. To further elucidate pathomechanism of NBOMes-induced rhabdomyolysis, we treated zebrafish with a similar designer drug, 2-(4-methyl-2, 5-dimethoxyphenyl)-NBOMe (25D-NBOMe). Zebrafish treated with a designer drug, 25D-NBOMe, were examined survival rate and were analyzed skeletal muscle degeneration by birefringence. They were also analyzed expression levels of 5-HT2A and 5-HT2C receptors and ryanodine receptor. The 25D-NBOMe-treated fish showed decreased survival rate and skeletal muscle degeneration detected by birefringence mimicking to those of 25B-NBOMe-treated fish. We revealed that 25D-NBOMe induced up-regulation of the expression of 5-HT2A and 5-HT2C receptors, and rhabdomyolysis was inhibited by the 5-HT2A receptor antagonist, aripiprazole and 5-HT2C receptor antagonist, SB242084. Moreover, ryanodine receptor expression was up-regulated in 25D-NBOMe-treated fish as compared to that of untreated fish, and the up-regulated expression of ryanodine receptor in 25D-NBOMe-treated fish was improved with co-treatment aripiprazole and SB242084. Our findings suggest that multiple 5-HT receptors have important roles in NBOMes-induced rhabdomyolysis together with other serotonin-related symptoms. Zebrafish is a highly useful model for therapeutic studies of rhabdomyolysis induced by psychoactive designer drugs.