Cannabinoid-induced motor incoordination through the cerebellar CB 1 receptor in mice

Abstract

Cannabinoids are known to impair motor function in humans and laboratory animals. We have observed dose-dependent motor incoordination in mice evaluated by rotorod following direct intracerebellar (icb) microinjection of synthetic cannabinoid agonists CP55,940 (5–25 μg) and HU-210 (1.56–6.25 μg), through permanently implanted stainless steel guide cannulas. The motor incoordination was marked at 15, 35 and 55 min post-microinjection. The motor incoordination elicited by HU-210 (6.25 μg) and CP55,940 (20 μg) was significantly blocked by the CB 1 receptor-selective antagonist SR141716A (25 μg icb), indicating mediation by a cerebellar CB 1 receptor. Further direct evidence of CB 1 mediation was obtained through a CB 1 receptor antisense/mismatch oligodeoxynucleotide approach (3 μg/12 h; total of six doses). Mice treated with intracerebellar antisense had a significantly diminished motor incoordination response to intracerebellar CP55,940 15 μg compared to mice that received intracerebellar mismatch or no prior treatment. Also, the response to intracerebellar CP55,940 in the CB 1 mismatch-treated mice did not differ from the mice that received only CP55,940. A separate study using a cerebellar tissue punching technique, following intracerebellar [ 3H]-CP55,940 microinjection, confirmed that cannabinoid drug dispersion following microinjections was exclusively confined to the cerebellum. Microinjection of CP55,940 (20 μg) into the hippocampus, an area with a large density of CB 1 receptors, did not impair motor coordination. Taken together, these results indicate that cannabinoid-induced motor impairment occurs by activation of a CB 1 receptor in the cerebellum. The participation of other brain motor areas in cannabinoid-induced motor incoordination will require future study.