Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice

Adolescence represents a developmental period with the highest risk for initiating cannabis use. Little is known about whether genetic variation in the endocannabinoid system alters mesolimbic reward circuitry to produce vulnerability to the rewarding properties of the exogenous cannabinoid Δ9-tetrahydrocannabinol (THC). Using a genetic knock-in mouse model (FAAHC/A) that biologically recapitulates the human polymorphism associated with problematic drug use, we find that in adolescent female mice, but not male mice, this FAAH polymorphism enhances the mesolimbic dopamine circuitry projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and alters cannabinoid receptor 1 (CB1R) levels at inhibitory and excitatory terminals in the VTA. These developmental changes collectively increase vulnerability of adolescent female FAAHC/A mice to THC preference that persists into adulthood. Together, these findings suggest that this endocannabinoid genetic variant is a contributing factor for increased susceptibility to cannabis dependence in adolescent females.

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The Endocannabinoid System in the Central Nervous System: Emphasis on the Role of the Mitochondrial Cannabinoid Receptor 1 (mtCB1R)

NeuroPsychopharmacotherapy ◽

10.1007/978-3-319-56015-1_461-1 ◽

2021 ◽

pp. 1-23

Author(s):

Marisol Maya-López ◽

Cecilia Zazueta ◽

Socorro Retana-Márquez ◽

Syed F. Ali ◽

Cimen Karasu ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Cannabinoid Receptor ◽

Endocannabinoid System ◽

Cannabinoid Receptor 1 ◽

The Central Nervous System

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THC-induced behavioral stereotypy in zebrafish as a model of psychosis-like behavior

Scientific Reports ◽

10.1038/s41598-021-95016-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Amelia Dahlén ◽

Mahdi Zarei ◽

Adam Melgoza ◽

Mahendra Wagle ◽

Su Guo

Keyword(s):

Nmda Receptor ◽

Cannabinoid Receptor ◽

Repetitive Behavior ◽

Endocannabinoid System ◽

Adult Zebrafish ◽

Acute Effects ◽

Cannabinoid Receptor 1 ◽

Cannabinoid Receptor 2 ◽

High Doses ◽

Underlying Mechanisms

AbstractHigh doses of the Cannabis constituent Δ9-tetrahydrocannabinol (THC) increase the risk of psychosis in humans. Highly accessible animal models are needed to address underlying mechanisms. Using zebrafish with a conserved endocannabinoid system, this study investigates the acute effects of THC on adult zebrafish behavior and the mechanisms involved. A concentration-dependent THC-induced behavioral stereotypy akin to THC’s effect in rats and the psychotropics phencyclidine and ketamine in zebrafish was established. Distinctive circular swimming during THC-exposure was measured using a novel analytical method that we developed, which detected an elevated Repetition Index (RI) compared to vehicle controls. This was reduced upon co-administration of N-methyl-D-aspartate (NMDA) receptor agonist NMDA, suggesting that THC exerts its effects via biochemical or neurobiological mechanisms associated with NMDA receptor antagonism. Co-treatment of γ‐aminobutyric acid receptor antagonist pentylenetetrazol also showed signs of reducing the RI. Since THC-induced repetitive behavior remained in co-administrations with cannabinoid receptor 1 inverse agonist AM251, the phenotype may be cannabinoid receptor 1-independent. Conversely, the inverse cannabinoid receptor 2 agonist AM630 significantly reduced THC-induced behavioral stereotypy, indicating cannabinoid receptor 2 as a possible mediator. A significant reduction of the THC-RI was also observed by the antipsychotic sulpiride. Together, these findings highlight this model’s potential for elucidating the mechanistic relationship between Cannabis and psychosis.

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Role of endocannabinoid system in the pathogenesis of obesity: how can we help a patient? From theory to practice

Russian Medical Inquiry ◽

10.32364/2587-6821-2020-4-6-382-389 ◽

2020 ◽

Vol 4 (6) ◽

pp. 382-389

Author(s):

V.A. Dudareva ◽

◽

M.L. Maksimov ◽

I.G. Djadikova ◽

A.A. Zveginceva ◽

...

Keyword(s):

Metabolic Syndrome ◽

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Endocannabinoid System ◽

Medical Society ◽

Cannabinoid Receptor 1 ◽

Peripheral Tissues ◽

Theory To Practice

Obesity that results in various metabolic disorders is one of the central concerns of modern healthcare system. Only 4% to 5% of patients with metabolic syndrome achieve favorable outcomes without any additional pharmacotherapy. Therefore, many patients require weight-loss drugs in addition to non-pharmacological treatments. The endocannabinoid system and the drugs that affect its functions receive a widespread attention of medical society due to its effects on behavioral and cerebral functions and its potential use as a therapeutic “target” in various peripheral and neurological psychiatric disorders. Among known to date cannabinoid receptors, type 1 receptors play a role in the development of obesity. It was demonstrated that the blockade of these receptors in the hypothalamus reduces appetite, inhibits adipocyte activation in peripheral tissues, prevents lipogenesis, and increases the level of adiponectin. The result is the decreased levels of atherogenic lipoproteins and improved insulin resistance. This article addresses the results of fundamental and clinical studies on Dietressa, a drug composed of affine-purified antibodies to cannabinoid receptor 1. Case report of a patient with obesity that analyzes pharmaceutical and non-pharmaceutical treatment approaches is described.KEYWORDS: obesity, metabolic syndrome, diet, endocannabinoid system, cannabinoids, cannabinoid receptors, affine-purified antibodies.FOR CITATION: Dudareva V.A., Maksimov M.L., Djadikova I.G. et al. Role of endocannabinoid system in the pathogenesis of obesity: how can we help a patient? From theory to practice. Russian Medical Inquiry. 2020;4(6):382–389. DOI: 10.32364/2587-6821-2020-4-6-382-389.

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The cannabinoid receptor 1 gene (CNR1) and multiple sclerosis: an association study in two case-control groups from Spain

Multiple Sclerosis Journal ◽

10.1177/1352458509355071 ◽

2009 ◽

Vol 16 (2) ◽

pp. 139-146 ◽

Cited By ~ 22

Author(s):

E. Ramil ◽

AJ Sánchez ◽

P. González-Pérez ◽

A. Rodríguez-Antigüedad ◽

N. Gómez-Lozano ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cannabinoid Receptor ◽

Endocannabinoid System ◽

Case Control ◽

Genotype Distribution ◽

Cannabinoid Receptor 1 ◽

Control Groups ◽

Gene Encoding ◽

Significant Difference ◽

Cnr1 Gene

Different studies point to the implication of the endocannabinoid system in multiple sclerosis (MS) and animal models of MS. The purpose of this study was to evaluate a possible association of MS with polymorphic markers at the CNR1 gene, encoding the cannabinoid 1 (CB1) receptor. We have performed a genetic analysis of an AAT repeat microsatellite localized in the downstream region of the CNR1 gene, in two case—control groups of MS patients and healthy controls (HC) from Spain (Madrid and Bilbao). MS patients with primary progressive MS (PPMS) had more commonly long ((AAT) ≥13) alleles and genotypes with a significant difference for genotype 7/8 in Madrid (p = 0.043) and in the sum of both groups (p = 0.016); short alleles were less frequently found in PPMS with a significant difference for allele 5 in the analysis of both groups together (p = 0.039). In patients with relapsing MS, no consistent differences in allele and genotype distribution were found. Disease severity and progression was unrelated to AAT repeat variations. In conclusion, long (AAT) ≥13 CNR1 genotypes could behave as risk factors for PPMS.

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PO-065 The Role and Mechanism of Endocannabinoid System in Exercise-induced Antinociception

Exercise Biochemistry Review ◽

10.14428/ebr.v1i3.10853 ◽

2018 ◽

Vol 1 (3) ◽

Author(s):

Guoqin Xu ◽

Hong Zhao

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Exercise Intensity ◽

Cannabinoid Receptor ◽

Endocannabinoid System ◽

The Body ◽

Cannabinoid Receptor 1 ◽

Cannabinoid Receptor 2 ◽

The Central Nervous System ◽

Exercise Induced

Objective As we all know, exercise can enhance the will, improve the mood, and counteract the bad feelings of the body, but the cause and mechanism of action have not been clear. The endocannabinoid system is an important regulatory system in the central nervous system that regulates cognition, mood and behavior. Endocannabinoids can exert physiological regulation through cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). Cannabinoid receptors are widely distributed in the body and participate in the regulation of anti-nociceptive signals at multiple levels. This study will explore the role and mechanism of the endocannabinoid system in exercise-induced antinociception by literature research methods. Methods Using endocannabinoid, exercise/sports and antinociception or emotion as keywords, using Pubmed, Medline, and Embase databases to search for nearly 15 years of research literature and the literatures from cross-references of journals, after excluding the literature that is not relevant to the research content, the 12 articles included were analyzed. Results Exercise can activate the endocannabinoid system, the degree of activation is related to exercise intensity, and high-intensity exercise significantly increases endocannabinoid levels in the human body. Cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) are widely distributed in the nervous system including the central nervous system and the peripheral nervous system. When exercise activates the endocannabinoid system, the increased endocannabinoid in the circulatory system activates CB1 and CB2 receptors, promotes hyperpolarization of the nervous system cells, reduces the rate of excitable cell release, and inhibits neurotransmitters, and reduce nociceptive impulses, thereby the body produces anti-nociception. Pretreatment with endocannabinoid metabolic enzyme inhibitors (MAFP, JZL184) and endocannabinoid reuptake inhibitors (VDM11) can be extended and enhanced the antinociceptive effect of exercise. Pretreatment with endocannabinoid receptor antagonists (AM251 and AM630) will inhibit the antinociception induced by aerobic exercise in mechanical and thermal nociceptive tests. Conclusions Exercise can enhance the level of circulating endocannabinoids, activate the endocannabinoid system through endocannabinoid receptors, and then induce the body to produce anti-nociceptive effects. The degree of activation is related to exercise intensity. Studying the role and mechanism of the endocannabinoid system in exercise-induced antinociception can provide a theoretical basis for exercise to improve depression, anxiety and other emotions, improve the sense of life and prevent mental disorders.

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Pharmacophore-based Virtual Screening From Phytocannabinoids for Anti-obesity Activity

10.21203/rs.3.rs-633011/v1 ◽

2021 ◽

Author(s):

Lenir C. Correia ◽

Jaderson V. Ferreira ◽

Henrique B. Lima ◽

Guilherme M. Silva ◽

Carlos H. T. P. da Silva ◽

...

Keyword(s):

Virtual Screening ◽

Cannabis Sativa ◽

Cannabinoid Receptor ◽

Binding Free Energy ◽

Endocannabinoid System ◽

Mean Square ◽

Cannabinoid Receptor 1 ◽

Long Period ◽

Cannabinoid Compounds ◽

Pharmacological Target

Abstract Search for new pharmacological alternatives for obesity is based on the design and development of compounds that can aid in weight loss so that they can be used safely and effectively over a long period while maintaining their function. The endocannabinoid system is related to obesity by increasing orexigenic signals and reducing satiety signals. Cannabis sativa is a medicinal plant of polypharmaceutical potential that has been widely studied for various medicinal purposes. The in silico evaluation of their natural cannabinoids (also called phytocannabinoids) for anti-obesity purpose stems from the existence of synthetic cannabinoid compounds that have already presented this result, but which did not guarantee patient safety. In order to find new molecules from C. sativa phytocannabinoids, with the potential to interact with the pharmacological target cannabinoid receptor 1, a pharmacophore-based virtual screening was performed, including the evaluation of physicochemical, pharmacokinetic, toxicological predictions and molecular docking. The results obtained from the ZINC12 database pointed to Zinc 69 (ZINC33053402) and Zinc 70 (ZINC19084698) molecules as promising anti-obesity agents. Molecular Dynamics (MD) studies discloses that both complexes were stable by analyzing the RMSD (Root Mean Square Deviation) values, and the binding free energy values demonstrate that the selected structures can interact and inhibit their catalytic activity.

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A Role for Peripheral Anandamide and 2-Arachidonoylglycerol in Short-Term Food Intake and Orexigenic Hypothalamic Responses in a Species with Continuous Nutrient Delivery

Nutrients ◽

10.3390/nu13103587 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3587

Author(s):

Isabel van Ackern ◽

Angela Kuhla ◽

Björn Kuhla

Keyword(s):

Food Intake ◽

Food Deprivation ◽

Cannabinoid Receptor ◽

Endocannabinoid System ◽

Related Protein ◽

Cannabinoid Receptor 1 ◽

Short Term ◽

Nutrient Delivery ◽

Increase Food Intake ◽

Agouti Related Protein

The endocannabinoid system (ECS) plays a pivotal role in the complex control and regulation of food intake. Pharmacological ECS activation could improve health in energy-deficient stages by increasing food intake, at least in intermittent feeders. However, knowledge of the mechanism regulating appetite in species with continued nutrient delivery is incomplete. The objectives of this pilot study were to investigate the effect of the intraperitoneal (i.p.) administration of the endocannabinoids (ECs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) on food intake, plasma EC concentrations and hypothalamic orexigenic signaling, and to study how the circulatory EC tone changes in response to short-term food deprivation in dairy cows, a species with continuous nutrient delivery. The administration of EC resulted in higher food intake during the first hour after treatment. Plasma AEA concentrations were significantly increased 2.5 h after AEA injection, whereas plasma 2-AG concentrations remained unchanged 2.5 h after 2-AG injection. The hypothalamic immunoreactivity of cannabinoid receptor 1, agouti-related protein, and orexin-A was not affected by either treatment; however, neuropeptide Y and agouti-related protein mRNA abundances were downregulated in the arcuate nucleus of AEA-treated animals. Short-term food deprivation increased plasma 2-AG, while plasma AEA remained unchanged. In conclusion, i.p.-administered 2-AG and AEA increase food intake in the short term, but only AEA accumulates in the circulation. However, plasma 2-AG concentrations are more responsive to food deprivation than AEA.

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Functional Genetic Variation of the Cannabinoid Receptor 1 and Cannabis Use Interact on Prefrontal Connectivity and Related Working Memory Behavior

Neuropsychopharmacology ◽

10.1038/npp.2014.213 ◽

2014 ◽

Vol 40 (3) ◽

pp. 640-649 ◽

Cited By ~ 32

Author(s):

Marco Colizzi ◽

Leonardo Fazio ◽

Laura Ferranti ◽

Annamaria Porcelli ◽

Rita Masellis ◽

...

Keyword(s):

Working Memory ◽

Genetic Variation ◽

Cannabinoid Receptor ◽

Cannabis Use ◽

Cannabinoid Receptor 1 ◽

Functional Genetic Variation

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Cannabinoid Receptor 1 Influences Chromatin Remodeling in Mouse Spermatids by Affecting Content of Transition Protein 2 mRNA and Histone Displacement

Endocrinology ◽

10.1210/en.2010-0133 ◽

2010 ◽

Vol 151 (10) ◽

pp. 5017-5029 ◽

Cited By ~ 46

Author(s):

Teresa Chioccarelli ◽

Giovanna Cacciola ◽

Lucia Altucci ◽

Sheena E. M. Lewis ◽

Luke Simon ◽

...

Keyword(s):

Chromatin Remodeling ◽

Cannabinoid Receptor ◽

Endocannabinoid System ◽

Reproductive Function ◽

Principal Component ◽

Sperm Chromatin ◽

Sperm Dna Fragmentation ◽

Cannabinoid Receptor 1 ◽

Sperm Dna Damage ◽

Sperm Dna

Marijuana smokers and animals treated with Δ9-tetrahydrocannabinol, the principal component of marijuana, show alterations of sperm morphology suggesting a role for cannabinoids in sperm differentiation and/or maturation. Because the cannabinoid receptor 1 (CNR1) activation appears to play a pivotal role in spermiogenesis, the developmental stage where DNA is remodeled, we hypothesized that CNR1 receptors might also influence chromatin quality in sperm. We used Cnr1 null mutant (Cnr1−/−) mice to study the possible role of endocannabinoids on sperm chromatin during spermiogenesis. We demonstrated that CNR1 activation regulated chromatin remodeling of spermatids by either increasing Tnp2 levels or enhancing histone displacement. Comparative analysis of wild-type, Cnr1+/−, and Cnr1−/− animals suggested the possible occurrence of haploinsufficiency for Tnp2 turnover control by CNR1, whereas histone displacement was disrupted to a lesser extent. Furthermore, flow cytometry analysis demonstrated that the genetic loss of Cnr1 decreased sperm chromatin quality and was associated with sperm DNA fragmentation. This damage increased during epididymal transit, from caput to cauda. Collectively, our results show that the expression/activity of CNR1 controls the physiological alterations of DNA packaging during spermiogenesis and epididymal transit. Given the deleterious effects of sperm DNA damage on male fertility, we suggest that the reproductive function of marijuana users may also be impaired by deregulation of the endogenous endocannabinoid system.

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