Convulsant doses of abused synthetic cannabinoid receptor agonists AB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA and JWH-018 do not elicit electroencephalographic (EEG) seizures in male mice

Abstract

Rationale: Synthetic cannabinoid receptor agonists (SCRAs) are found in illicit smoking products, such as "K2" or "Spice." Convulsions are commonly reported adverse effects of SCRAs but are poorly understood.

Objectives: We determined convulsant effects of SCRAs AB-PINACA, and 5F-ADB-PINACA in adult male NIH Swiss mice, and then determined if convulsant effects of AB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, and JWH-018 elicited seizure-like effects using EEG.

Methods: Mice were administered SCRAs or pentylenetetrazole (PTZ) and placed in observation chambers where convulsant effects were scored. The capacity of the CB1R antagonist rimonabant, the benzodiazepine diazepam, or the non-specific CYP450 inhibitor 1-aminobenzotriazole (1-ABT) to attenuate convulsant effects was determined. Other mice were prepared with EEG headmounts to ascertain whether observed convulsions occurred concurrently with seizure-like effects by assessing root-mean-square (RMS) power, high amplitude EEG spike analysis, and videography.

Results: Mice receiving AB-PINACA or 5F-ADB-PINACA exhibited dose-dependent convulsant effects that were blocked by 10 mg/kg rimonabant pretreatment but not by pretreatment with 10 mg/kg diazepam; these convulsant effects were not altered in the presence of 100 mg/kg 1-ABT. Repeated administration of 10 mg/kg AB-PINACA and 3 mg/kg 5F-ADB-PINACA produced partial tolerance to convulsant effects but did not lead to cross-tolerance to PTZ-induced convulsions. In EEG studies, convulsant doses of AB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, and JWH-018 did not produce seizures concomitantly with convulsions.

Conclusions: These data extend previous findings of convulsant effects of SCRAs and suggest that convulsant effects of AB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, and JWH-018 are CB1R-mediated but are not associated with electroencephalographic seizures. These results further suggest that benzodiazepines may not effectively treat convulsions elicited by SCRA use in humans.

Keywords: CB1 receptor; Convulsions; EEG; Synthetic cannabinoids; Tolerance.