Motor-like Tics are Mediated by CB2 Cannabinoid Receptor-dependent and Independent Mechanisms Associated with Age and Sex

Abstract

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.

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