Motor-like Tics are Mediated by CB2 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/ß-hydrolase domain-containing 6 (ABHD6) expression levels. CB2 receptors are required to reduce 5-HT2A/2C-induced tics in adults. HU-308 has an off-target effect which increases 5-HT2A/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-HT2A/2C-induced reduction in endocannabinoid catabolic enzyme expression level may explain the increased endocannabinoids' levels in patients with TS.

Different responses of repetitive behaviours in juvenile and young adult mice to Δ9 -tetrahydrocannabinol and cannabidiol may affect decision making for Tourette syndrome.

BACKGROUND AND PURPOSE: Medicinal cannabis is in increasing use by patients with Tourette syndrome, a neuropsychiatric disorder that affects about 1% of the general population and has a childhood onset. However, the pharmacological effects of Δ9 -tetrahydrocannabinol (Δ9 -THC) and cannabidiol (CBD) have not been systematically screened or compared between juvenile and young adult rodents in a model of Tourette syndrome. EXPERIMENTAL APPROACH: The administration of 2,5-dimethoxy-4-iodoamphetamine (DOI) increases head twitch response (HTR) and ear scratch response (ESR) and has been proposed as an animal model useful to respectively study motor tics and premonitory urges associated with tic disorders. KEY RESULTS: Comparing the potency of Δ9 -THC to inhibit DOI-induced repetitive behaviours, the rank order was ESR > grooming > HTR versus ESR = grooming > HTR in young adult versus juvenile mice. Δ9 -THC (5 mg·kg-1 ) induced severe adverse effects in the form of cataleptic behaviour in control mice and significantly increased ESR in juveniles. The pharmacological effects of CBD have not been studied in models of Tourette syndrome. In juveniles, CBD had no effect on DOI-induced ESR and grooming behaviours. CBD alone induced side effects, significantly increasing the frequency of HTR in juveniles and young adults. CONCLUSION AND IMPLICATIONS: Δ9 -THC efficaciously reverses peripheral but not central motor tics. Δ9 -THC may reduce ambulatory movements and evoke premonitory urges in some paediatric patients. The small "therapeutic window" in juveniles suggests that CBD may not effectively treat motor tics in children and may even exacerbate tics in a population of patients with Tourette syndrome.