Interactions Between Alcohol and the Endocannabinoid System

Kunos, George

doi:10.1111/acer.14306

Cited by 33 publications

(35 citation statements)

References 184 publications

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“…The role of the endocannabinoid (eCB) neurotransmitter system in the regulation of several alcohol-related behaviors is well documented and summarizable with cannabinoid CB 1 receptor antagonists/inverse agonists inhibiting and cannabinoid CB 1 receptor agonists stimulating alcohol drinking, operant alcohol selfadministration, and reinstatement of alcohol seeking in rats and mice. [1][2][3][4] The adverse neuropsychiatric ef-fects of the prototypic cannabinoid CB 1 receptor antagonist/inverse agonist, rimonabant, have regrettably prevented a proper translation to patients affected by alcohol use disorder (AUD) of the large number of remarkably consistent rodent studies reporting its ''antialcohol'' properties.…”

Section: Introductionmentioning

confidence: 99%

Reducing Effect of Cannabidiol on Alcohol Self-Administration in Sardinian Alcohol-Preferring Rats

Maccioni

Bratzu

Carai

et al. 2022

Cannabis and Cannabinoid Research

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Introduction: Cannabidiol (CBD) is a major cannabinoid extracted from Cannabis sativa with no abuse potential. Data from recent rodent studies suggest that amelioration of alcohol-motivated behaviors may be one of the numerous pharmacological effects of CBD. This study was designed to contribute to this research, assessing the effect of CBD on operant oral alcohol self-administration in selectively bred Sardinian alcohol-preferring (sP) rats, a validated animal model of excessive alcohol consumption. In addition, this study investigated the effect of CBD on operant self-administration of a highly palatable chocolate solution in Wistar rats. Materials and Methods: Male sP rats were trained to lever respond for alcohol (15% v/v) under the fixed ratio 4 (FR4) schedule of reinforcement. Once lever responding had stabilized, rats were exposed to test sessions under the FR4 and progressive ratio (PR) schedules of reinforcement. Test sessions were preceded by acute treatment with CBD (0, 6.25, 12.5, and 25 mg/kg or 0, 25, 50, and 100 mg/kg, i.p.; each dose range was tested in an independent experiment). Male Wistar rats were trained to lever respond for a chocolate solution (5% w/v chocolate powder) under the FR10 schedule of reinforcement. Once lever responding had stabilized, rats were exposed to test sessions under the same schedule. Test sessions were preceded by acute treatment with CBD (0, 6.25, 12.5, and 25 mg/kg or 0, 25, 50, and 100 mg/kg, i.p., in two independent experiments). Results: Under the FR schedule, treatment with doses of CBD ‡ 12.5 mg/kg markedly reduced lever responding for alcohol and amount of self-administered alcohol. Under the PR schedule, treatment with CBD produced a slight tendency toward a decrease in lever responding and breakpoint for alcohol. Finally, no dose of CBD affected lever responding for the chocolate solution and amount of self-administered chocolate solution. Discussion: These results extend previous data on CBD ability to affect alcohol-motivated behaviors to an animal model of genetically-determined proclivity to high alcohol consumption. Because of the predictive validity of sP rats, these results may be of relevance in view of possible future studies testing CBD in patients affected by alcohol use disorder.

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Section: Introductionmentioning

confidence: 99%

Reducing Effect of Cannabidiol on Alcohol Self-Administration in Sardinian Alcohol-Preferring Rats

Maccioni

Bratzu

Carai

et al. 2022

Cannabis and Cannabinoid Research

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“…30,31 AEA is produced from N-arachidonoyl-phosphatidylethanolamine by N-acyl-phosphatidylethanolamine-specific phospholipase D, and fatty acid amide hydrolase mediates degradation of AEA. 32,33 In the liver, CB 1 R activation contributes to various liver diseases, such as non-alcoholic fatty liver disease, alcoholic steatosis, inflammation, and fibrosis, whereas cannabinoid receptor 2 (CB 2 R) activation ameliorates the progression of liver disease by inhibiting activation of Kupffer cells. 30,[34][35][36][37][38] Interestingly, both receptors are expressed in most hepatic cells including hepatocytes, HSCs, and immune cells.…”

Section: Endocannabinoid Systemmentioning

confidence: 99%

Oxidative stress and glutamate excretion in alcoholic steatosis: Metabolic synapse between hepatocyte and stellate cell

2020

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Chronic alcohol consumption induces the development of alcoholic steatosis in the liver, which is one of the most widespread liver diseases worldwide. During general alcohol metabolism, hepatocytes generate mitochondria- and cytochrome P450 2E1 (CYP2E1)-mediated reactive oxygen species (ROS) whose accumulation elicits activation of the hepatic anti-oxidant system, including glutathione (GSH). However, chronic alcohol consumption decreases GSH generation through cysteine deficiency by suppressing the methionine cycle and trans-sulfuration system, whereas it turns on an alternative defense pathway, such as the xCT transporter, to compensate for GSH shortage. The xCT transporter mediates the uptake of cystine coupled to the efflux of glutamate, leading to an increase in blood glutamate. In response to the elevated glutamate in the liver, the expression of metabotropic glutamate receptor 5 (mGluR5) is up-regulated in hepatic stellate cells (HSCs) along with enhanced production of 2-arachidonoylglycerol, which in turn stimulates cannabinoid receptor 1 (CB1R) on neighboring hepatocytes to increase de novo lipogenesis. On the other hand, blockade of mGluR5 and CB1R attenuates alcoholic steatosis. Interestingly, although the increased expression of CYP2E1-mediated xCT and ROS generation are mainly observed at the perivenous area (zone 3), fat accumulation is mostly detected at hepatic zone 2. To resolve this discrepancy, this review summarizes recent advances on glutamate/mGluR5-derived alcoholic steatosis and zone-dependently different responses to alcohol intake. In addition, the bidirectional loop pathway and its unique metabolic synapse between hepatocytes and HSCs are discussed.

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“…In addition, alcohol-mediated activation of CB1 receptor signaling can induce ERRγ-mediated alcoholic fatty liver [9]. These findings indicate that the CB1 receptor plays a critical role in the pathogenesis of alcoholic liver disease (ALD) including alcoholic fatty liver, liver injury, and liver fibrosis [2].…”

Section: Introductionmentioning

confidence: 99%

“…The endocannabinoid system includes two G protein-coupled receptors: cannabinoid receptor type 1 (CB1) and type 2 (CB2) [1]. The CB1 receptor is expressed in the heart, brain, vascular tissue, and liver, while the CB2 receptor is expressed primarily in cells of immune and hematopoietic systems [2]. It was reported that endocannabinoids, anandamide, and 2-arachidonoylglycerol (2-AG) are associated with neuronal, immune, metabolic, vascular, and reproductive functions.…”

Section: Introductionmentioning

confidence: 99%

Orphan Nuclear Receptor ERRγ Is a Transcriptional Regulator of CB1 Receptor-Mediated TFR2 Gene Expression in Hepatocytes

Kim

Choi

Park

et al. 2021

IJMS

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Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is an important transcription factor modulating gene transcription involved in endocrine control of liver metabolism. Transferrin receptor 2 (TFR2), a carrier protein for transferrin, is involved in hepatic iron overload in alcoholic liver disease (ALD). However, TFR2 gene transcriptional regulation in hepatocytes remains largely unknown. In this study, we described a detailed molecular mechanism of hepatic TFR2 gene expression involving ERRγ in response to an endocannabinoid 2-arachidonoylglycerol (2-AG). Treatment with 2-AG and arachidonyl-2′-chloroethylamide, a selective cannabinoid receptor type 1 (CB1) receptor agonist, increased ERRγ and TFR2 expression in hepatocytes. Overexpression of ERRγ was sufficient to induce TFR2 expression in both human and mouse hepatocytes. In addition, ERRγ knockdown significantly decreased 2-AG or alcohol-mediated TFR2 gene expression in cultured hepatocytes and mouse livers. Finally, deletion and mutation analysis of the TFR2 gene promoter demonstrated that ERRγ directly modulated TFR2 gene transcription via binding to an ERR-response element. This was further confirmed by chromatin immunoprecipitation assay. Taken together, these results reveal a previously unrecognized role of ERRγ in the transcriptional regulation of TFR2 gene expression in response to alcohol.

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Interactions Between Alcohol and the Endocannabinoid System

Cited by 33 publications

References 184 publications

Reducing Effect of Cannabidiol on Alcohol Self-Administration in Sardinian Alcohol-Preferring Rats

Reducing Effect of Cannabidiol on Alcohol Self-Administration in Sardinian Alcohol-Preferring Rats

Oxidative stress and glutamate excretion in alcoholic steatosis: Metabolic synapse between hepatocyte and stellate cell

Orphan Nuclear Receptor ERRγ Is a Transcriptional Regulator of CB1 Receptor-Mediated TFR2 Gene Expression in Hepatocytes

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