Hyperreflexia induced by XLR-11 smoke is caused by the pyrolytic degradant

Abstract

Purpose: Some of the synthetic cannabinoids, often found in recreational drugs of the herbal form, reportedly induce a generalized seizure in drug abusers immediately after smoking. However, it is still unclear what elicits the sensorimotor responses, particularly in the case of hyperreflexia or excitatory behavior during the synthetic cannabinoid exposure. The purpose of this study was to explore the mechanism underlying the hyperreflexia induced by smoke intoxication of XLR-11 [(1-(5-fluoropentyl)-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone]. Methods: Locomotor activity and body temperature of mice were measured using an implanted Nano-Tag device. The intensity of catalepsy was determined by the bar test. The extracellular dopamine levels in the nucleus accumbens and glutamate levels in the hippocampus were measured by in vivo microdialysis using electrochemical detector-coupled high-performance liquid chromatography and by in vivo enzyme-based biosensor method, respectively. Results: Mice exposed to the smoke of XLR-11 exhibited hyperreflexia at the very early phase, followed by hypothermia and catalepsy. The XLR-11 smoke contained XLR-11 and XLR-11 degradant at a ratio of approximately 1:25. Mice treated intraperitoneally with XLR-11 degradant at a dose comparable to the smoke inhalation experiment showed a hyperreflexic effect immediately after the treatment, but XLR-11 showed no such effect. The effects of XLR-11 degradant were significantly suppressed by pretreatment with AM-251, a CB1 receptor antagonist. Extracellular dopamine and glutamate levels showed no evidence of involvement in the XLR-11 degradant-induced hyperreflexia; on the other hand gabapentin, a GABAergic antiepileptic, significantly suppressed the enhanced locomotor activity. Conclusions: The hyperreflexic effect of XLR-11 degradant is mediated by the CB1 receptor and possibly by GABAergic function.