Cannabidiol Modulates the Motor Profile and NMDA Receptor-related Alterations Induced by Ketamine

Cannabidiol (CBD) is a non-addictive ingredient of cannabis with antipsychotic potential, while ketamine (KET), an uncompetitive NMDA receptor inhibitor, has been extensively used as a psychotomimetic. Only few studies have focused on the role of CBD on the KET-induced motor profile, while no study has investigated the impact of CBD on KET-induced alterations in NMDA receptor subunit expression and ERK phosphorylation state, in brain regions related to the neurobiology and treatment of schizophrenia. Therefore, the aim of the present study is to evaluate the role of CBD on KET-induced motor response and relevant glutamatergic signaling in the prefrontal cortex, the nucleus accumbens, the dorsal and ventral hippocampus. The present study demonstrated that CBD pre-administration did not reverse KET-induced short-lasting hyperactivity, but it prolonged it over time. CBD alone decreased motor activity at the highest dose tested (30 mg/kg) while KET increased motor activity at the higher doses (30, 60 mg/kg). Moreover, KET induced regionally-dependent alterations in NR1 and NR2B expression and ERK phosphorylation that were reversed by CBD pre-administration. Interestingly, in the nucleus accumbens KET per se reduced NR2B and p-ERK levels, while the CBD/KET combination increased NR2B and p-ERK levels, as compared to control. This study is the first to show that CBD prolongs KET-induced motor stimulation and restores KET-induced effects on glutamatergic signaling and neuroplasticity-related markers. These findings contribute to the understanding of CBD effects on the behavioral and neurobiological profiles of psychotogenic KET.