CB1 Receptor Silencing Attenuates Ketamine-Induced Hyperlocomotion Without Compromising Its Antidepressant-Like...

Introduction: The antidepressant properties of ketamine have been extensively demonstrated in experimental and clinical settings. However, the psychotomimetic side effects still limit its wider use as an antidepressant. It was recently observed that endocannabinoids are inolved in ketamine induced reward properties. As an increase in endocannabinoid signaling induces antidepressant effects, this study aimed to investigate the involvement of cannabinoid type 1 receptors (CB₁R) in the antidepressant and psychostimulant effects induced by ketamine. Methods: We tested the effects of genetic and pharmacological inhibition of CB₁R in the hyperlocomotion and antidepressant-like properties of ketamine. The effects of ketamine (10-20 mg/kg) were assessed in the open-field and the forced swim tests (FSTs) in CB₁R knockout (KO) and wild-type (WT) mice (male and female), and mice pre-treated with rimonabant (CB₁R antagonist, 3-10 mg/kg). Results: We found that the motor hyperactivity elicited by ketamine was impaired in CB₁R male and female KO mice. A similar effect was observed upon pharmacological blockade of CB₁R in WT mice. However, genetic CB₁R deletion did not modify the antidepressant effect of ketamine in male mice submitted to the FST. Surprisingly, pharmacological blockade of CB₁R induced an antidepressant-like effect in both male and female mice, which was not further potentiated by ketamine. Conclusions: Our results support the hypothesis that CB₁R mediate the psychostimulant side effects induced by ketamine, but not its antidepressant properties.