Sex-dependent pharmacological profiles of the synthetic cannabinoid MMB-Fubinaca

摘要

Synthetic cannabinoids have emerged as novel psychoactive substances with damaging consequences for public health. They exhibit high affinity at the cannabinoid type-1 (CB1) receptor and produce similar and often more potent effects as other CB(1)receptor agonists. However, we are still far from a complete pharmacological understanding of these compounds. In this study, by using behavioral, molecular, pharmacological, and electrophysiological approaches, we aimed at characterizing severalin vitroandin vivopharmacological effects of the synthetic cannabinoid MMB-Fubinaca (also known as AMB-Fubinaca or FUB-AMB), a particular synthetic cannabinoid. MMB-Fubinaca stimulates CB(1)receptor-mediated functional coupling to G-proteins in mouse and human brain preparations in a similar manner as the CB(1)receptor agonist WIN55,512-2 but with a much greater potency. Both drugs similarly activate the CB(1)receptor-dependent extracellular signal-regulated kinase (ERK) pathway. Notably,in vivoadministration of MMB-Fubinaca in mice induced greater behavioral and electrophysiological effects in male than in female mice in a CB(1)receptor-dependent manner. Overall, these data provide a solid pharmacological profiling of the effects of MMB-Fubinaca and important information about the mechanisms of action underlying its harmful impact in humans. At the same time, they reinforce the significant sexual dimorphism of cannabinoid actions, which will have to be taken into account in future animal and clinical studies.