The endocannabinoidome in neuropsychiatry: Opportunities and potential risks

Gerwyn Morris; Ken Walder; Stefan Kloiber; Paul Amminger; Michael Berk; Chiara C Bortolasci; Michael Maes; Basant K Puri; Andre F Carvalho

doi:10.1016/j.phrs.2021.105729

The endocannabinoidome in neuropsychiatry: Opportunities and potential risks

Pharmacol Res. 2021 Aug:170:105729. doi: 10.1016/j.phrs.2021.105729. Epub 2021 Jun 11.

Authors

Gerwyn Morris¹, Ken Walder², Stefan Kloiber³, Paul Amminger⁴, Michael Berk⁵, Chiara C Bortolasci¹, Michael Maes⁶, Basant K Puri⁷, Andre F Carvalho⁸

Affiliations

¹ Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia.
² Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Deakin University, Centre for Molecular and Medical Research, School of Medicine, Geelong, Australia.
³ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 33 Ursula Franklin Street, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁴ Orygen, Parkville, Victoria, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
⁵ Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia.
⁶ Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria.
⁷ Cambridge Advanced Research (C.A.R.), Cambridge, UK.
⁸ Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia. Electronic address: andrefc7@hotmail.com.

PMID: 34119623
DOI: 10.1016/j.phrs.2021.105729

Abstract

The endocannabinoid system (ECS) comprises two cognate endocannabinoid receptors referred to as CB1R and CB2R_. ECS dysregulation is apparent in neurodegenerative/neuro-psychiatric disorders including but not limited to schizophrenia, major depressive disorder and potentially bipolar disorder. The aim of this paper is to review mechanisms whereby both receptors may interact with neuro-immune and neuro-oxidative pathways, which play a pathophysiological role in these disorders. CB1R is located in the presynaptic terminals of GABAergic, glutamatergic, cholinergic, noradrenergic and serotonergic neurons where it regulates the retrograde suppression of neurotransmission. CB1R plays a key role in long-term depression, and, to a lesser extent, long-term potentiation, thereby modulating synaptic transmission and mediating learning and memory. Optimal CB1R activity plays an essential neuroprotective role by providing a defense against the development of glutamate-mediated excitotoxicity, which is achieved, at least in part, by impeding AMPA-mediated increase in intracellular calcium overload and oxidative stress. Moreover, CB1R activity enables optimal neuron-glial communication and the function of the neurovascular unit. CB2R receptors are detected in peripheral immune cells and also in central nervous system regions including the striatum, basal ganglia, frontal cortex, hippocampus, amygdala as well as the ventral tegmental area. CB2R upregulation inhibits the presynaptic release of glutamate in several brain regions. CB2R activation also decreases neuroinflammation partly by mediating the transition from a predominantly neurotoxic "M1" microglial phenotype to a more neuroprotective "M2" phenotype. CB1R and CB2R are thus novel drug targets for the treatment of neuro-immune and neuro-oxidative disorders including schizophrenia and affective disorders.

Keywords: Affective disorders; Bipolar disorder; Depression; Endocannabinoid receptors; Neuro-immune; Neurodegeneration; Neuroscience; Neurotoxicity; Oxidative stress; Psychiatry; Schizophrenia.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Anti-Inflammatory Agents / pharmacology
Brain / drug effects
Brain / metabolism*
Brain / physiopathology
Central Nervous System Agents / therapeutic use
Endocannabinoids / metabolism*
Humans
Memory
Mental Disorders / drug therapy
Mental Disorders / metabolism*
Mental Disorders / physiopathology
Mental Disorders / psychology
Neurodegenerative Diseases / drug therapy
Neurodegenerative Diseases / metabolism*
Neurodegenerative Diseases / physiopathology
Neurodegenerative Diseases / psychology
Neuroinflammatory Diseases / drug therapy
Neuroinflammatory Diseases / metabolism*
Neuroinflammatory Diseases / physiopathology
Neuroinflammatory Diseases / psychology
Neuronal Plasticity
Receptor, Cannabinoid, CB1 / drug effects
Receptor, Cannabinoid, CB1 / metabolism*
Receptor, Cannabinoid, CB2 / drug effects
Receptor, Cannabinoid, CB2 / metabolism*
Synaptic Transmission

Substances

Anti-Inflammatory Agents
Central Nervous System Agents
Endocannabinoids
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2