Convulsant effects of high efficacy synthetic cannabinoid JWH‐018 in mice

Abstract

Medical cannabis has apparent efficacy in controlling seizure in treatment‐resistant epilepsy, particularly in children. In contrast, abuse of high efficacy synthetic CB1 agonists (SCBs) can result in significant toxicity, including morbidity not typically associated with marijuana, such as seizure. Here, the convulsant effects of the aminoalkylindole SCB JWH‐018 were investigated in mice, and compared with those of the classical chemical convulsant pentylenetetrazole (PTZ) using an observational rating scale. JWH‐018 and PTZ dose‐dependently elicited convulsant effects in mice. The CB1 antagonist / inverse agonist rimonabant blocked convulsant effects of JWH‐018, but not those of PTZ. Pretreatment with Δ9‐THC dose‐dependently blunted the convulsant effects of JWH‐018, but did not alter PTZ‐induced convulsions. Daily administration of JWH‐018 for five consecutive days resulted in tolerance to its convulsant effecs, but daily treatment with PTZ increased its convulsant effects. Finally, no cross‐tolerance was observed when PTZ was administered to mice previously made tolerant to JWH‐018‐elicited convulsions. These data suggest that CB1 agonists can elicit convulsant effects in the mouse, although intrinsic efficacy is likely to be an important factor. These studies supported, in part, by an NIGMS IDeA Program award (GM110702), by the UAMS Translational Research Institute (RR029884), and by T32 DA022981. KDC and COC received Summer Undergraduate Research Fellowships from the American Society of Pharmacology and Experimental Therapeutics.