PT  - JOURNAL ARTICLE
AU  - Catheryn D. Wilson
AU  - Sherrica Tai
AU  - Laura Ewing
AU  - Jasmine Crane
AU  - Taylor Lockhart
AU  - Azure L Yarbrough
AU  - Ryoichi Fujiwara
AU  - Anna Radominska-Pandya
AU  - William E. Fantegrossi
TI  - Convulsant effects of abused synthetic cannabinoids JWH-018 and 5F-AB-PINACA are mediated by agonist actions at CB1 receptors in mice
AID  - 10.1124/jpet.118.251157
DP  - 2018 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.118.251157
4099  - http://jpet.aspetjournals.org/content/early/2018/11/21/jpet.118.251157.short
4100  - http://jpet.aspetjournals.org/content/early/2018/11/21/jpet.118.251157.full
AB  - 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 ∆9-tetrahydrocannabinol (THC), full CB1R agonist SCBs JWH-018 and 5F-AB-PINACA, and classical chemical convulsant pentylenetetrazol (PTZ) using an observational rating scale in mice. THC did not elicit convulsions, but both SCBs did so as effectively 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 PTZ-elicited convulsions without altering SCB-induced convulsant effects. Repeated administration of a sub-threshold 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 non-selective inhibition of CYP450s with 1-aminobenzotriazole (1-ABT) 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, while 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.