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Endocannabinoids, Cannabinoids and Psychiatry: Biological Mechanisms
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Endocannabinoids, Cannabinoids and Psychiatry: Biological Mechanisms

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 December 2020) | Viewed by 19299

Special Issue Editors

Prof. Aron Weller

E-Mail Website
Guest Editor
Department of Psychology and the Gonda Brain Research Center, Bar Ilan University, Ramat Gan 5290002, Israel
Interests: endocannabinoids; biological psychiatry; epigenetics; developmental psychobiology; behavioral neuroscience; psychoneuroendocrinology; animal models of obesity, binge eating, depression, infant–mother attachment, emotion-regulation
Special Issues, Collections and Topics in MDPI journals
Dr. Sari Goldstein Ferber

E-Mail Website
Guest Editor
Department of Psychology and the Gonda Brain Research Center, Bar Ilan University, Ramat Gan 5290002, Israel
Interests: endocannabinoids; early development; psychopathology; mental health; psychoneuroendocrinology; epigenetics; stress exposure; randomized controlled clinical trials
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

During the past decade, scientific knowledge on the role and contributions of endocannabinoids and cannabinoids to the optimal functioning of the human brain has advanced considerably. Currently, the endocannabinoid system is regarded, based on recent scientific findings, as a modulatory system of brain connectivity and top-down bottom-up structural pathways, protecting against extreme inhibitory or extreme excitatory cortical and sub-cortical conditions. Such extreme conditions have been suggested to underlie psychopathology. Additionally, the stabilizing effect of cannabinoids in cases of mood disorders, anxiety, depression and schizophrenia, social phobia, personality disorders, bipolar disorders, and post-traumatic stress disorder has been shown in recent years by various researchers including those using animal models. Research on the role of endocannabinoids in the development of psychiatric disorders, their course and remission has also recently advanced. The field of clinical trials on cannabinoid treatment in psychiatry is just emerging. This timely issue will be among the first to publish novel data on endocannabinoids and cannabinoids in various psychiatric disorders. This is a call for papers on underlying biological, including molecular and neural, mechanisms of endocannabinoid and cannabinoid functions in psychiatric disorders based on animal models, in vitro and ex vivo models and human clinical trials. Data on age and gender, as well as early development and life span considerations of endocannabinoids and cannabinoids in psychiatric disorders are also encouraged. Epigenetic and genetic vulnerabilities interacting with the environmental impact related to the endocannabinoid system in psychopathology are also welcome. In this context, magnetic resonance and other imaging studies and studies on crosstalk with other neurotransmitter systems are among the top interests of this issue. The vulnerability of the endocannabinoid system under stressful conditions will also be a focus of this issue, including interactions of this system with stress exposure. Risk factors for the development of psychiatric disorders related to the endocannabinoid system and identified within the fields of brain research, epigenetic, genetic, and molecular research are important components to be included in this issue. Cutting-edge reviews are also invited. We note that non-randomized clinical research and survey studies are not suitable for IJMS.

Prof. Aron Weller
Dr. Sari Goldstein Ferber
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • endocannabinoids
  • cannabinoids
  • psychiatry
  • neural mechanisms
  • molecular mechanisms
  • epigenetics
  • imaging
  • psychopathology
  • stress

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Published Papers (6 papers)

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Research

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16 pages, 4380 KiB  
Article
Distinct Activity of Endocannabinoid-Hydrolyzing Enzymes MAGL and FAAH in Key Regions of Peripheral and Central Nervous System Implicated in Migraine
by Adriana Della Pietra, Rashid Giniatullin and Juha R. Savinainen
Int. J. Mol. Sci. 2021, 22(3), 1204; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031204 - 26 Jan 2021
Cited by 15 | Viewed by 2775
Abstract
In migraine pain, cannabis has a promising analgesic action, which, however, is associated with side psychotropic effects. To overcome these adverse effects of exogenous cannabinoids, we propose migraine pain relief via activation of the endogenous cannabinoid system (ECS) by inhibiting enzymes degrading endocannabinoids. [...] Read more.
In migraine pain, cannabis has a promising analgesic action, which, however, is associated with side psychotropic effects. To overcome these adverse effects of exogenous cannabinoids, we propose migraine pain relief via activation of the endogenous cannabinoid system (ECS) by inhibiting enzymes degrading endocannabinoids. To provide a functional platform for such purpose in the peripheral and central parts of the rat nociceptive system relevant to migraine, we measured by activity-based protein profiling (ABPP) the activity of the main endocannabinoid-hydrolases, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). We found that in trigeminal ganglia, the MAGL activity was nine-fold higher than that of FAAH. MAGL activity exceeded FAAH activity also in DRG, spinal cord and brainstem. However, activities of MAGL and FAAH were comparably high in the cerebellum and cerebral cortex implicated in migraine aura. MAGL and FAAH activities were identified and blocked by the selective and potent inhibitors JJKK-048/KML29 and JZP327A, respectively. The high MAGL activity in trigeminal ganglia implicated in the generation of nociceptive signals suggests this part of ECS as a priority target for blocking peripheral mechanisms of migraine pain. In the CNS, both MAGL and FAAH represent potential targets for attenuation of migraine-related enhanced cortical excitability and pain transmission. Full article
(This article belongs to the Special Issue Endocannabinoids, Cannabinoids and Psychiatry: Biological Mechanisms)
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21 pages, 2045 KiB  
Article
Alterations in Rat Accumbens Dopamine, Endocannabinoids and GABA Content During WIN55,212-2 Treatment: The Role of Ghrelin
by Chrysostomos Charalambous, Marek Lapka, Tereza Havlickova, Kamila Syslova and Magdalena Sustkova-Fiserova
Int. J. Mol. Sci. 2021, 22(1), 210; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010210 - 28 Dec 2020
Cited by 11 | Viewed by 2429
Abstract
The endocannabinoid/CB1R system as well as the central ghrelin signalling with its growth hormone secretagogoue receptors (GHS-R1A) are importantly involved in food intake and reward/reinforcement processing and show distinct overlaps in distribution within the relevant brain regions including the hypothalamus (food intake), the [...] Read more.
The endocannabinoid/CB1R system as well as the central ghrelin signalling with its growth hormone secretagogoue receptors (GHS-R1A) are importantly involved in food intake and reward/reinforcement processing and show distinct overlaps in distribution within the relevant brain regions including the hypothalamus (food intake), the ventral tegmental area (VTA) and the nucleus accumbens (NAC) (reward/reinforcement). The significant mutual interaction between these systems in food intake has been documented; however, the possible role of ghrelin/GHS-R1A in the cannabinoid reinforcement effects and addiction remain unclear. Therefore, the principal aim of the present study was to investigate whether pretreatment with GHS-R1A antagonist/JMV2959 could reduce the CB1R agonist/WIN55,212-2–induced dopamine efflux in the nucleus accumbens shell (NACSh), which is considered a crucial trigger impulse of the addiction process. The synthetic aminoalklylindol cannabinoid WIN55,212-2 administration into the posterior VTA induced significant accumbens dopamine release, which was significantly reduced by the 3 mg/kg i.p. JMV2959 pretreatment. Simultaneously, the cannabinoid-increased accumbens dopamine metabolic turnover was significantly augmented by the JMV2959 pretreament. The intracerebral WIN55,212-2 administration also increased the endocannabinoid arachidonoylethanolamide/anandamide and the 2-arachidonoylglycerol/2-AG extracellular levels in the NACSh, which was moderately but significantly attenuated by the JMV2959 pretreatment. Moreover, the cannabinoid-induced decrease in accumbens γ-aminobutyric acid/gamma-aminobutyric acid levels was reversed by the JMV2959 pretreatment. The behavioural study in the LABORAS cage showed that 3 mg/kg JMV2959 pretreatment also significantly reduced the systemic WIN55,212-2-induced behavioural stimulation. Our results demonstrate that the ghrelin/GHS-R1A system significantly participates in the rewarding/reinforcing effects of the cannabinoid/CB1 agonist that are involved in cannabinoid addiction processing. Full article
(This article belongs to the Special Issue Endocannabinoids, Cannabinoids and Psychiatry: Biological Mechanisms)
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19 pages, 5710 KiB  
Article
Cannabinoid Type 1 Receptor is Undetectable in Rodent and Primate Cerebral Neural Stem Cells but Participates in Radial Neuronal Migration
by Yury M. Morozov, Ken Mackie and Pasko Rakic
Int. J. Mol. Sci. 2020, 21(22), 8657; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228657 - 17 Nov 2020
Cited by 6 | Viewed by 2347
Abstract
Cannabinoid type 1 receptor (CB1R) is expressed and participates in several aspects of cerebral cortex embryonic development as demonstrated with whole-transcriptome mRNA sequencing and other contemporary methods. However, the cellular location of CB1R, which helps to specify molecular mechanisms, [...] Read more.
Cannabinoid type 1 receptor (CB1R) is expressed and participates in several aspects of cerebral cortex embryonic development as demonstrated with whole-transcriptome mRNA sequencing and other contemporary methods. However, the cellular location of CB1R, which helps to specify molecular mechanisms, remains to be documented. Using three-dimensional (3D) electron microscopic reconstruction, we examined CB1R immunolabeling in proliferating neural stem cells (NSCs) and migrating neurons in the embryonic mouse (Mus musculus) and rhesus macaque (Macaca mulatta) cerebral cortex. We found that the mitotic and postmitotic ventricular and subventricular zone (VZ and SVZ) cells are immunonegative in both species while radially migrating neurons in the intermediate zone (IZ) and cortical plate (CP) contain CB1R-positive intracellular vesicles. CB1R immunolabeling was more numerous and more extensive in monkeys compared to mice. In CB1R-knock out mice, projection neurons in the IZ show migration abnormalities such as an increased number of lateral processes. Thus, in radially migrating neurons CB1R provides a molecular substrate for the regulation of cell movement. Undetectable level of CB1R in VZ/SVZ cells indicates that previously suggested direct CB1R-transmitted regulation of cellular proliferation and fate determination demands rigorous re-examination. More abundant CB1R expression in monkey compared to mouse suggests that therapeutic or recreational cannabis use may be more distressing for immature primate neurons than inferred from experiments with rodents. Full article
(This article belongs to the Special Issue Endocannabinoids, Cannabinoids and Psychiatry: Biological Mechanisms)
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Review

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16 pages, 1056 KiB  
Review
Discovering the Lost Reward: Critical Locations for Endocannabinoid Modulation of the Cortico–Striatal Loop That Are Implicated in Major Depression
by Sari Goldstein Ferber, Aron Weller, Gal Yadid and Alexander Friedman
Int. J. Mol. Sci. 2021, 22(4), 1867; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041867 - 13 Feb 2021
Cited by 5 | Viewed by 4031
Abstract
Depression, the most prevalent psychiatric disorder in the Western world, is characterized by increased negative affect (i.e., depressed mood, cost value increase) and reduced positive affect (i.e., anhedonia, reward value decrease), fatigue, loss of appetite, and reduced psychomotor activity except for cases of [...] Read more.
Depression, the most prevalent psychiatric disorder in the Western world, is characterized by increased negative affect (i.e., depressed mood, cost value increase) and reduced positive affect (i.e., anhedonia, reward value decrease), fatigue, loss of appetite, and reduced psychomotor activity except for cases of agitative depression. Some forms, such as post-partum depression, have a high risk for suicidal attempts. Recent studies in humans and in animal models relate major depression occurrence and reoccurrence to alterations in dopaminergic activity, in addition to other neurotransmitter systems. Imaging studies detected decreased activity in the brain reward circuits in major depression. Therefore, the location of dopamine receptors in these circuits is relevant for understanding major depression. Interestingly, in cortico–striatal–dopaminergic pathways within the reward and cost circuits, the expression of dopamine and its contribution to reward are modulated by endocannabinoid receptors. These receptors are enriched in the striosomal compartment of striatum that selectively projects to dopaminergic neurons of substantia nigra compacta and is vulnerable to stress. This review aims to show the crosstalk between endocannabinoid and dopamine receptors and their vulnerability to stress in the reward circuits, especially in corticostriatal regions. The implications for novel treatments of major depression are discussed. Full article
(This article belongs to the Special Issue Endocannabinoids, Cannabinoids and Psychiatry: Biological Mechanisms)
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23 pages, 1210 KiB  
Review
Elevated Brain Fatty Acid Amide Hydrolase Induces Depressive-Like Phenotypes in Rodent Models: A Review
by Dorsa Rafiei and Nathan J. Kolla
Int. J. Mol. Sci. 2021, 22(3), 1047; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031047 - 21 Jan 2021
Cited by 12 | Viewed by 4409
Abstract
Altered activity of fatty acid amide hydrolase (FAAH), an enzyme of the endocannabinoid system, has been implicated in several neuropsychiatric disorders, including major depressive disorder (MDD). It is speculated that increased brain FAAH expression is correlated with increased depressive symptoms. The aim of [...] Read more.
Altered activity of fatty acid amide hydrolase (FAAH), an enzyme of the endocannabinoid system, has been implicated in several neuropsychiatric disorders, including major depressive disorder (MDD). It is speculated that increased brain FAAH expression is correlated with increased depressive symptoms. The aim of this scoping review was to establish the role of FAAH expression in animal models of depression to determine the translational potential of targeting FAAH in clinical studies. A literature search employing multiple databases was performed; all original articles that assessed FAAH expression in animal models of depression were considered. Of the 216 articles that were screened for eligibility, 24 articles met inclusion criteria and were included in this review. Three key findings emerged: (1) FAAH expression is significantly increased in depressive-like phenotypes; (2) genetic knockout or pharmacological inhibition of FAAH effectively reduces depressive-like behavior, with a dose-dependent effect; and (3) differences in FAAH expression in depressive-like phenotypes were largely localized to animal prefrontal cortex, hippocampus and striatum. We conclude, based on the animal literature, that a positive relationship can be established between brain FAAH level and expression of depressive symptoms. In summary, we suggest that FAAH is a tractable target for developing novel pharmacotherapies for MDD. Full article
(This article belongs to the Special Issue Endocannabinoids, Cannabinoids and Psychiatry: Biological Mechanisms)
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19 pages, 366 KiB  
Review
Do Adolescent Exposure to Cannabinoids and Early Adverse Experience Interact to Increase the Risk of Psychiatric Disorders: Evidence from Rodent Models
by Anna Portugalov and Irit Akirav
Int. J. Mol. Sci. 2021, 22(2), 730; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020730 - 13 Jan 2021
Cited by 4 | Viewed by 2689
Abstract
There have been growing concerns about the protracted effects of cannabis use in adolescents on emotion and cognition outcomes, motivated by evidence of growing cannabis use in adolescents, evidence linking cannabis use to various psychiatric disorders, and the increasingly perceived notion that cannabis [...] Read more.
There have been growing concerns about the protracted effects of cannabis use in adolescents on emotion and cognition outcomes, motivated by evidence of growing cannabis use in adolescents, evidence linking cannabis use to various psychiatric disorders, and the increasingly perceived notion that cannabis is harmless. At the same time, studies suggest that cannabinoids may have therapeutic potential against the impacts of stress on the brain and behavior, and that young people sometimes use cannabinoids to alleviate feelings of depression and anxiety (i.e., “self-medication”). Exposure to early adverse life events may predispose individuals to developing psychopathology in adulthood, leading researchers to study the causality between early life factors and cognitive and emotional outcomes in rodent models and to probe the underlying mechanisms. In this review, we aim to better understand the long-term effects of cannabinoids administered in sensitive developmental periods (mainly adolescence) in rodent models of early life stress. We suggest that the effects of cannabinoids on emotional and cognitive function may vary between different sensitive developmental periods. This could potentially affect decisions regarding the use of cannabinoids in clinical settings during the early stages of development and could raise questions regarding educating the public as to potential risks associated with cannabis use. Full article
(This article belongs to the Special Issue Endocannabinoids, Cannabinoids and Psychiatry: Biological Mechanisms)
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