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However, the effect of HU-308, a selective CB<jats:sub>2<\/jats:sub> receptor agonist, on repetitive behaviors has not been investigated. The effects of 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced motor-like tics and \u0394<jats:sup>9<\/jats:sup>-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<jats:sub>2<\/jats:sub> receptor knockout (CB<jats:sub>2<\/jats:sub><jats:sup>\u2212\/\u2212<\/jats:sup>) mice, and in the presence\/absence of DOI or SR141716A, a CB<jats:sub>1<\/jats:sub> receptor antagonist\/inverse agonist. The frequency of DOI-induced repetitive behaviors was higher in CB<jats:sub>2<\/jats:sub><jats:sup>\u2212\/\u2212<\/jats:sup> than in wildtype mice. HU-308 increased DOI-induced ESR and grooming behavior in adult CB<jats:sub>2<\/jats:sub><jats:sup>\u2212\/\u2212<\/jats:sup> 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<jats:sub>2<\/jats:sub> receptor and GPR55, but reduced fatty acid amide hydrolase (FAAH) and \u03b1\/\u03b2-hydrolase domain-containing 6 (ABHD6) expression levels. CB<jats:sub>2<\/jats:sub> receptors are required to reduce 5-HT<jats:sub>2A\/2C<\/jats:sub>-induced tics in adults. HU-308 has an off-target effect which increases 5-HT<jats:sub>2A\/2C<\/jats:sub>-induced motor-like tics in adult female mice. The increased HTR in juveniles induced by selective CB<jats:sub>2<\/jats:sub> receptor agonists suggests that stimulation of the CB<jats:sub>2<\/jats:sub> receptor may generate motor tics in children. Sex differences suggest that the CB<jats:sub>2<\/jats:sub> receptor may contribute to the prevalence of TS in boys. The 5-HT<jats:sub>2A\/2C<\/jats:sub>-induced reduction in endocannabinoid catabolic enzyme expression level may explain the increased endocannabinoids\u2019 levels in patients with TS.<\/jats:p>","DOI":"10.1007\/s12035-022-02884-6","type":"journal-article","created":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T04:02:41Z","timestamp":1654488161000},"page":"5070-5083","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Motor-like Tics are Mediated by CB2 Cannabinoid Receptor-dependent and Independent Mechanisms Associated with Age and Sex"],"prefix":"10.1007","volume":"59","author":[{"given":"Victoria","family":"Gorberg","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronika","family":"Borisov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iain R.","family":"Greig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger G.","family":"Pertwee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"McCaffery","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3364-5134","authenticated-orcid":false,"given":"Sharon","family":"Anavi-Goffer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,6,6]]},"reference":[{"issue":"12","key":"2884_CR1","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1038\/nrneurol.2011.167","volume":"7","author":"KSP McNaught","year":"2011","unstructured":"McNaught KSP, Mink JW (2011) Advances in understanding and treatment of Tourette syndrome. 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