Motor-like Tics are Mediated by CB 2 Cannabinoid Receptor-dependent and Independent Mechanisms Associated with Age and Sex

Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) inhibits tics in individuals with Tourette syndrome (TS). Δ⁹-THC has similar affinities for CB₁/CB₂ cannabinoid receptors. However, the effect of HU-308, a selective CB₂ receptor agonist, on repetitive behaviors has not been investigated. The effects of 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced motor-like tics and Δ⁹-THC were studied with gene analysis. The effects of HU-308 on head twitch response (HTR), ear scratch response (ESR), and grooming behavior were compared between wildtype and CB₂ receptor knockout (CB₂^-/-) mice, and in the presence/absence of DOI or SR141716A, a CB₁ receptor antagonist/inverse agonist. The frequency of DOI-induced repetitive behaviors was higher in CB₂^-/- than in wildtype mice. HU-308 increased DOI-induced ESR and grooming behavior in adult CB₂^-/- mice. In juveniles, HU-308 inhibited HTR and ESR in the presence of DOI and SR141716A. HU-308 and beta-caryophyllene significantly increased HTR. In the left prefrontal cortex, DOI increased transcript expression of the CB₂ receptor and GPR55, but reduced fatty acid amide hydrolase (FAAH) and α/β-hydrolase domain-containing 6 (ABHD6) expression levels. CB₂ receptors are required to reduce 5-HT_2A/2C-induced tics in adults. HU-308 has an off-target effect which increases 5-HT_2A/2C-induced motor-like tics in adult female mice. The increased HTR in juveniles induced by selective CB₂ receptor agonists suggests that stimulation of the CB₂ receptor may generate motor tics in children. Sex differences suggest that the CB₂ receptor may contribute to the prevalence of TS in boys. The 5-HT_2A/2C-induced reduction in endocannabinoid catabolic enzyme expression level may explain the increased endocannabinoids’ levels in patients with TS.