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 ketamine-induced short-lasting hyperactivity, but it prolonged it over time. CBD alone decreased motor activity at the highest dose tested (30 mg/kg) while ketamine 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.
Keywords: Cannabidiol, ERK1/2, NMDA receptors, ketamine, motor activity, rats
Copyright © 2020. Published by Elsevier Ltd.
Conflict of interest statement
Conflict of interest The authors declare no conflicts of interest
Cannabidiol Improves Cognitive Impairment and Reverses Cortical Transcriptional Changes Induced by Ketamine, in Schizophrenia-Like Model in Rats.Mol Neurobiol. 2020 Mar;57(3):1733-1747. doi: 10.1007/s12035-019-01831-2. Epub 2019 Dec 11.PMID: 31823199
Ketamine-induced hypnosis and neuroplasticity in mice is associated with disrupted p-MEK/p-ERK sequential activation and sustained upregulation of survival p-FADD in brain cortex: Involvement of GABAA receptor.Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jan 10;88:121-131. doi: 10.1016/j.pnpbp.2018.07.006. Epub 2018 Jul 10.PMID: 30003929
Cannabidiol Counteracts Amphetamine-Induced Neuronal and Behavioral Sensitization of the Mesolimbic Dopamine Pathway through a Novel mTOR/p70S6 Kinase Signaling Pathway.J Neurosci. 2016 May 4;36(18):5160-9. doi: 10.1523/JNEUROSCI.3387-15.2016.PMID: 27147666 Free PMC article.
[Glutaminergic hypothesis of schizophrenia: clinical research studies with ketamine].Encephale. 2001 Jan-Feb;27(1):53-9.PMID: 11294039 Review. French.
Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug.Braz J Med Biol Res. 2006 Apr;39(4):421-9. doi: 10.1590/s0100-879×2006000400001. Epub 2006 Apr 3.PMID: 16612464 Review.