The Effect of SERM/CB2 Receptor Modulators on Repetitive Behaviours in Juvenile and Young Adult Mice May Have Implications for Tourette Syndrome Treatment

Abstract

Tourette syndrome (TS) is a neurodevelopmental disorder, with a male-to-female ratio of approximately 3:1, characterised by involuntary tics, frequently comorbid with conditions such as obsessive–compulsive disorder (OCD). Some patients exhibit limited responsiveness to standard medications, necessitating alternative therapeutic strategies. Clomiphene, a selective oestrogen receptor modulator (SERM), emerged as a potential candidate. However, raloxifene and bazedoxifene, which exhibit distinct chemical structures from clomiphene, present dual modulation not only as oestrogen receptor modulators but also as inverse agonists of the cannabinoid CB2 receptor. The present study compared the efficacy of clomiphene, raloxifene, and bazedoxifene in alleviating TS/OCD-like behaviours in mice. The findings revealed dose, sex, and age differences in the effects of raloxifene, and to a lesser extent of bazedoxifene, demonstrating potential therapeutic benefit for treating TS/OCD-like behaviours. The effects of raloxifene were compared in the presence of 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced or SR141716A-induced motor-like tics, premonitory urges-induced, and OCD-like behaviours in mice. DOI-induced juvenile male and female mice responded to raloxifene, while only adolescent DOI-induced females responded to raloxifene. These results suggest that SERM drugs that are also CB2 receptor antagonists/inverse-agonists may be a new class of drugs to reduce motor tics and OCD symptoms in patients with TS/OCD.