Endocannabinoid system in psychotic and mood disorders, a review of human studies.
02 Mar 2021-Progress in Neuro-psychopharmacology & Biological Psychiatry (Elsevier)-Vol. 106, pp 110096
TL;DR: Postmortem, peripheral, cerebrospinal fluid and in vivo imaging studies provide evidence for the role of the endocannabinoid system in both psychotic and mood disorders, and there is a clear need for investigation beyond the CB1 receptor in order to more fully elucidate the role.
Abstract: Despite widespread evidence of endocannabinoid system involvement in the pathophysiology of psychiatric disorders, our understanding remains rudimentary. Here we review studies of the endocannabinoid system in humans with psychotic and mood disorders. Postmortem, peripheral, cerebrospinal fluid and in vivo imaging studies provide evidence for the involvement of the endocannabinoid system in psychotic and mood disorders. Psychotic disorders and major depressive disorder exhibit alterations of brain cannabinoid CB1 receptors and peripheral blood endocannabinoids. Further, these changes may be sensitive to treatment status, disease state, and symptom severity. Evidence from psychotic disorder extend to endocannabinoid metabolizing enzymes in the brain and periphery, whereas these lines of evidence remain poorly developed in mood disorders. A paucity of studies examining this system in bipolar disorder represents a notable gap in the literature. Despite a growing body of productive work in this field of research, there is a clear need for investigation beyond the CB1 receptor in order to more fully elucidate the role of the endocannabinoid system in psychotic and mood disorders.
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TL;DR: The endocannabinoid system (ECS) comprises two cognate receptors referred to as CB1R and CB2R as discussed by the authors, which play an essential neuroprotective role by providing a defense against the development of glutamate-mediated excitotoxicity, which is achieved by impeding AMPA-mediated increase in intracellular calcium overload and oxidative stress.
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TL;DR: A summary of valid biological hypotheses of schizophrenia formulated based on risk factors and biomarkers, neurodevelopment, neuroplasticity, brain chemistry, and antipsychotic medication can be found in this article .
Abstract: Both the discovery of biomarkers of schizophrenia and the verification of biological hypotheses of schizophrenia are an essential part of the process of understanding the etiology of this mental disorder. Schizophrenia has long been considered a neurodevelopmental disease whose symptoms are caused by impaired synaptic signal transduction and brain neuroplasticity. Both the onset and chronic course of schizophrenia are associated with risk factors-induced disruption of brain function and the establishment of a new homeostatic setpoint characterized by biomarkers. Different risk factors and biomarkers can converge to the same symptoms of schizophrenia, suggesting that the primary cause of the disease can be highly individual. Schizophrenia-related biomarkers include measurable biochemical changes induced by stress (elevated allostatic load), mitochondrial dysfunction, neuroinflammation, oxidative and nitrosative stress, and circadian rhythm disturbances. Here is a summary of selected valid biological hypotheses of schizophrenia formulated based on risk factors and biomarkers, neurodevelopment, neuroplasticity, brain chemistry, and antipsychotic medication. The integrative neurodevelopmental-vulnerability-neurochemical model is based on current knowledge of the neurobiology of the onset and progression of the disease and the effects of antipsychotics and psychotomimetics and reflects the complex and multifactorial nature of schizophrenia.
9 citations
TL;DR: In this article, a standardized M. officinalis bark extract (MOE), enriched in honokiol, and its effect on animal mood behavioural tests and in an in vitro model of excitotoxicity was evaluated.
Abstract: Objectives The exposure of neurons to an excessive excitatory stimulation induces the alteration of the normal neuronal function. Mood disorders are among the first signs of alterations in the central nervous system function. Magnolia officinalis bark extract has been extensively used in the traditional medicine systems of several countries, showing several pharmacological activities. Honokiol, the main constituent of M. officinalis, is a GABA modulator and a CB1 agonist, which is deeply investigated for its role in modulating mood disorders. Methods Thus, we evaluated the possible neuroprotective effect of a standardized M. officinalis bark extract (MOE), enriched in honokiol, and its effect on animal mood behavioural tests and in an in vitro model of excitotoxicity. Key findings MOE showed neuroprotective effect using SH-SY5Y cells, by normalizing brain-derived neurotrophic factor release. Then, we tested the effect of MOE in different behavioural tests evaluating anxiety and depression and we observed a selective anxiolytic-like effect. Finally, we confirmed the involvement of CB1 in the final effect of MOE by the co-administration of the CB1 antagonist, AM251. Conclusion These results suggest that MOE could be considered an effective and safe anxiolytic candidate with neuroprotective activity.
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TL;DR: In this article, a review examines the current state of evidence regarding the clinical potential of cannabinoid-based drugs as a treatment for schizophrenia, while discussing various limitations with the therapeutic approaches considered so far.
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References
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TL;DR: These functional CB2 receptors in the brainstem were activated by a CB2 receptor agonist, 2-arachidonoylglycerol, and by elevated endogenous levels of endocannabinoids, which also act at CB1 receptors.
Abstract: The presence and function of CB2 receptors in central nervous system (CNS) neurons are controversial. We report the expression of CB2 receptor messenger RNA and protein localization on brainstem neurons. These functional CB2 receptors in the brainstem were activated by a CB2 receptor agonist, 2-arachidonoylglycerol, and by elevated endogenous levels of endocannabinoids, which also act at CB1 receptors. CB2 receptors represent an alternative site of action of endocannabinoids that opens the possibility of nonpsychotropic therapeutic interventions using enhanced endocannabinoid levels in localized brain areas.
1,466 citations
TL;DR: This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non- CB1, non-CB2 established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors.
Abstract: There are at least two types of cannabinoid receptors (CB1 and CB2). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ9-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB1, non-CB2 established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB1 and/or CB2 receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel “CB3” cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB1, non-CB2 pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB3 receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB1 receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB1/CB2 receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB1, non-CB2 cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.
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TL;DR: An introduction to the endocannabinoid system is provided with an emphasis on its role in synaptic plasticity and how the ECS is perturbed in schizophrenia.
698 citations
TL;DR: Research into the pharmacology of individual cannabinoids that began in the 1940s is concisely reviewed and it is described how this pharmacological research led to the discovery of cannabinoid CB1 and CB2 receptors and of endogenous ligands for these receptors.
Abstract: Research into the pharmacology of individual cannabinoids that began in the 1940s, several decades after the presence of a cannabinoid was first detected in cannabis, is concisely reviewed. Also described is how this pharmacological research led to the discovery of cannabinoid CB1 and CB2 receptors and of endogenous ligands for these receptors, to the development of CB1- and CB2-selective agonists and antagonists and to the realization that the endogenous cannabinoid systemhas significant roles in both health and disease, and that drugs which mimic, augment or block the actions of endogenously released cannabinoids must have important therapeutic applications. Some goals for future research are identified. British Journal of Pharmacology (2006) 147, S163–S171. doi:10.1038/sj.bjp.0706406
604 citations
TL;DR: There is the need for detailed anatomical studies of brain regions important in the therapeutic actions of drugs that modify the endocannabinoid system and the determination of the localization of the enzymes that synthesize, degrade, and transport the endOCannabinoids.
Abstract: CB1 cannabinoid receptors appear to mediate most, if not all of the psychoactive effects of delta-9-tetrahydrocannabinol and related compounds. This G protein-coupled receptor has a characteristic distribution in the nervous system: It is particularly enriched in cortex, hippocampus, amygdala, basal ganglia outflow tracts, and cerebellum—a distribution that corresponds to the most prominent behavioral effects of cannabis. In addition, this distribution helps to predict neurological and psychological maladies for which manipulation of the endocannabinoid system might be beneficial. CB1 receptors are primarily expressed on neurons, where most of the receptors are found on axons and synaptic terminals, emphasizing the important role of this receptor in modulating neurotransmission at specific synapses. While our knowledge of CB1 localization in the nervous system has advanced tremendously over the past 15 years, there is still more to learn. Particularly pressing is the need for (1) detailed anatomical studies of brain regions important in the therapeutic actions of drugs that modify the endocannabinoid system and (2) the determination of the localization of the enzymes that synthesize, degrade, and transport the endocannabinoids.
604 citations