Convulsant Effects of Abused Synthetic Cannabinoids JWH-018 and 5F-AB-PINACA Are Mediated by Agonist Actions at CB1 Receptors in Mice

Abstract

Convulsant effects of abused synthetic cannabinoid (SCB) drugs have been reported in humans and laboratory animals, but the mechanism of these effects is not known. We compared convulsant effects of partial CB1R agonist Δ 9 -tetrahydrocannabinol (THC), full CB1R agonist SCBs JWH-018 and 5F-AB-PINACA, and classic chemical convulsant pentylenetetrazol (PTZ) using an observational rating scale in mice. THC did not elicit convulsions, but both SCBs did so as effectively as and more potently than PTZ. SCB-elicited convulsions were attenuated by the CB1R antagonist rimonabant or by THC, or by dose regimens of THC and JWH-018, which downregulate and desensitize CB1Rs. None of these treatments altered the convulsant effects of PTZ, although diazepam attenuated PTZelicited convulsions without altering SCB-induced convulsant effects. Repeated administration of a subthreshold dose of PTZ kindled convulsant effects, but this was not observed with the SCBs, and no cross-kindling was observed. Repeated administration of the SCBs resulted in tolerance to convulsant effects, but no cross-tolerance to PTZ was observed. Inhibition on Phase I metabolism via nonselective inhibition of CYP450s with 1-aminobenzotriazole potentiated the hypothermic effects of the SCBs and protected against the convulsant effects of JWH-018, but not those of 5F-AB-PINACA or PTZ. Incubation of human liver microsomes with the SCBs showed that JWH-018 is eliminated via oxidation, whereas 5F-AB-PINACA is not. These studies suggest that SCB-elicited convulsions are mediated by high intrinsic efficacy at CB1Rs and that benzodiazepines may not be effective treatments. Finally, drug metabolism may dramatically modulate the convulsant effects of some, but not all, SCBs.

Differential activation of G-protein-mediated signalling by synthetic cannabinoid receptor agonists

“…Although this study does not identify which pathway contributes to the toxic effects observed following SCRA consumption, our data do provide valuable insights into SCRA-mediated stimulation and inhibition of cAMP signalling in vitro. Previous studies have shown that JWH-018-AM-2201-, 5F-AB-PINACA-, and CUMYL-4CN-BINACA-induced seizures are CB1-mediated in mice, which might explain some of the toxicity experienced by recreational users of these drugs [43,44,45,46,47,48,49]. Our data shows that SCRA-induced cAMP increase was abolished after SR141716A treatment, supporting the hypothesis that SCRAs Gαs-like effects were mediated through CB1…”

Differential activation of G protein‐mediated signaling by synthetic cannabinoid receptor agonists

“…Although this study does not identify which pathway contributes to the toxic effects observed following SCRA consumption, our data do provide valuable insights into SCRA‐mediated stimulation and inhibition of cAMP signaling in vitro. Previous studies have shown that JWH‐018‐ AM‐2201‐, 5F‐AB‐PINACA‐, and CUMYL‐4CN‐BINACA‐induced seizures are CB1‐mediated in mice, which might explain some of the toxicity experienced by recreational users of these drugs . Our data shows that SCRA‐induced cAMP increase was abolished after SR141716A treatment, supporting the hypothesis that SCRAs Gα s ‐like effects were mediated through CB1 receptor.…”

CUMYL-4CN-BINACA Is an Efficacious and Potent Pro-Convulsant Synthetic Cannabinoid Receptor Agonist

“…For example, PB-22, AB-CHMINACA, and MDMB-CHMICA have been associated with generalized seizures in humans (Gugelmann et al, 2014; Hermanns-Clausen et al, 2018). In mice, 10 mg/kg 5F-AB-PINACA produces convulsions, which can be reduced by 10 mg/kg SR141716 pretreatment (Wilson et al, 2019). AM-2201 (2 mg/kg, i.p).…”