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

Δ(9)-Tetrahydrocannabinol (Δ(9)-THC) inhibits tics in individuals with Tourette syndrome (TS). Δ(9)-THC has similar affinities for CB(1)/CB(2) cannabinoid receptors. However, the effect of HU-308, a selective CB(2) receptor agonist, on repetitive behaviors has not been investigated. The effects of 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced motor-like tics and Δ(9)-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 CB(2) receptor knockout (CB(2)(−/−)) mice, and in the presence/absence of DOI or SR141716A, a CB(1) receptor antagonist/inverse agonist. The frequency of DOI-induced repetitive behaviors was higher in CB(2)(−/−) than in wildtype mice. HU-308 increased DOI-induced ESR and grooming behavior in adult CB(2)(−/−) 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 CB(2) receptor and GPR55, but reduced fatty acid amide hydrolase (FAAH) and α/β-hydrolase domain-containing 6 (ABHD6) expression levels. CB(2) 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 CB(2) receptor agonists suggests that stimulation of the CB(2) receptor may generate motor tics in children. Sex differences suggest that the CB(2) 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-022-02884-6.