Hepatic Cannabinoid Receptor Type 1 Mediates Alcohol-Induced Regulation of Bile Acid Enzyme Genes Expression Via CREBH.

“In this study, we have investigated the effect of alcohol exposure on hepatic bile acid homeostasis and elucidated the mediatory roles of Cb1r and Crebh in this process.

We found that alcohol exposure or Cb1r-agonist 2-AG treatment increases hepatic bile acid synthesis and serum ALT, AST levels in vivo along with significant increase in Crebh gene expression and activation.

 Alcohol exposure activated Cb1r, Crebh, and perturbed bile acid homeostasis…

 Overall, our study demonstrates a novel regulatory mechanism of hepatic bile acid metabolism by alcohol via Cb1r-mediated activation of Crebh, and suggests that targeting Crebh can be of therapeutic potential in ameliorating alcohol-induced perturbation of bile acid homeostasis.”

http://www.ncbi.nlm.nih.gov/pubmed/23894352

Alcohol-cancer link stronger than ever – News

“Alcohol-cancer link stronger than ever”  http://health.msn.co.nz/healthnews/8689975/alcohol-cancer-link-stronger-than-ever

“Study supports alcohol, breast cancer link”  http://www.health.harvard.edu/blog/study-supports-alcohol-breast-cancer-link-201111033747

“Alcohol Use Linked to More Cancers”  http://articles.mercola.com/sites/articles/archive/2006/02/18/alcohol-use-linked-to-more-cancers.aspx#!

“The Alcoholic-Cancer Link: Study Shows Even One Drink a Day Could Be Risky”  http://www.everydayhealth.com/cancer/alcoholic-cancer-link-study-shows-one-drink-per-day-raises-risk.aspx

“Alcohol Behind Rise in Breast Cancer Among Women”  http://www.medindia.net/news/alcohol-behind-rise-in-breast-cancer-among-women-122089-1.htm

“Alcohol Linked to Cancer Risk in Women. Study Shows Even Low-to-Moderate Drinking Raises Risk of Cancer.”  http://women.webmd.com/news/20090224/alcohol-linked-to-cancer-risk-in-women

“Why Drinking Alcohol Is Linked to Breast Cancer”  http://www.sciencedaily.com/releases/2012/04/120423162245.htm

“Alcohol And Genetic Factors Linked To Breast Cancer Risk”  http://www.medicalnewstoday.com/articles/103911.php

“Alcohol Linked to Breast Cancer Diagnosis, Study Finds” http://www.foxnews.com/health/2011/11/01/alcohol-linked-to-breast-cancer-diagnosis-study-finds/

“Many cancer deaths traced to alcohol” http://www.foxnews.com/health/2013/02/15/many-cancer-deaths-traced-to-alcohol/

“Light drinking linked to breast cancer risk”  http://usatoday30.usatoday.com/news/health/medical/health/medical/breastcancer/story/2011-11-01/Light-drinking-linked-to-slight-breast-cancer-risk/51030414/1

“Moderate Drinking Linked to Breast Cancer”  http://www.livescience.com/4421-moderate-drinking-linked-breast-cancer.html

“Heavy Drinking Linked to Aggressive Prostate Cancer”  http://health.usnews.com/health-news/family-health/cancer/articles/2009/07/13/heavy-drinking-linked-to-aggressive-prostate-cancer

“Many Cancer Deaths Traced to Alcohol”  http://www.livescience.com/27259-alcohol-causes-cancer-deaths.html

“Alcohol Plays A Huge Role In Cancer Deaths In The U.S.”  http://www.medicalnewstoday.com/articles/256472.php

“Study Shows Link Between Alcohol & Breast Cancer”  http://www.nbc26.com/news/206493561.html

“Alcohol Consumption Boosts Breast Cancer Risk”  http://abcnews.go.com/blogs/health/2012/06/03/alcohol-consumption-boosts-breast-cancer-risk/

“Even Moderate Drinking Can Boost Chance of Breast Cancer Recurrence”  http://abcnews.go.com/Health/OnCallPlusBreastCancerNews/moderate-drinking-linked-breast-cancer-recurrence/story?id=9306082

“Breast cancer link to small amount of alcohol”  http://www.bbc.co.uk/news/health-15539450

“Alcohol link to bowel cancer risk”  http://news.bbc.co.uk/2/hi/6921998.stm

“Alcohol Linked To Breast Cancer”  http://www.cbsnews.com/8301-18563_162-529131.html

“Light drinking linked to breast cancer risk”  http://www.cbsnews.com/8301-500165_162-20128877/light-drinking-linked-to-breast-cancer-risk/

“Review describes link between alcohol consumption and breast cancer”  http://www.news-medical.net/news/20121024/Review-describes-link-between-alcohol-consumption-and-breast-cancer.aspx

“Breast cancer leading cause of alcohol-attributable death in New Zealand women” http://medicalxpress.com/news/2013-07-breast-cancer-alcohol-attributable-death-zealand.html

“Alcoholism is linked to higher rates of general and cancer-related deaths” http://medicalxpress.com/news/2011-11-alcoholism-linked-higher-cancer-related-deaths.html

“Smoking, heavy drinking linked to earlier onset of pancreatic cancer”  http://medicalxpress.com/news/2012-10-heavy-linked-earlier-onset-pancreatic.html

“Heavy alcohol consumption linked to lung cancer”   http://medicalxpress.com/news/2011-10-heavy-alcohol-consumption-linked-lung.html

“Alcohol Use Linked to Risk for Hormone-Sensitive Breast Cancers”  http://www.medscape.com/viewarticle/727432

“Alcohol Linked to Colorectal Cancer Risk”  http://www.medscape.com/viewarticle/749886

“Heavy Alcohol Use Linked to Colon Cancer Risk”  http://www.medscape.com/viewarticle/463001

“Link Between Pancreatic Cancer and Alcohol, Tobacco Use”  http://www.medscape.org/viewarticle/771688

“Heavy Drinking Linked to Pancreatic Cancer”  http://www.webmd.com/cancer/pancreatic-cancer/news/20110314/heavy-drinking-linked-to-pancreatic-cancer?page=2

“No Amount of Alcohol Is Safe. “Responsible drinking” has become a 21st-century mantra for how most people view alcohol consumption. But when it comes to cancer, no amount of alcohol is safe.” http://www.medscape.com/viewarticle/824237

“Even moderate drinking may substantially raise risk of dying from cancer: study”  http://www.nydailynews.com/life-style/health/moderate-drinking-raises-cancer-death-risk-study-article-1.1265529

“Light drinking linked to breast cancer, study finds”  http://www.washingtonpost.com/national/health-science/light-drinking-linked-to-breast-cancer-study-finds/2011/11/01/gIQASythdM_video.html

“A Drink a Day Raises Cancer Risk, Study Says”  http://www.bu.edu/today/2013/a-drink-a-day-raises-cancer-risk-study-says/

“Even a drink a day boosts cancer death risk, alcohol study finds”  http://www.nbcnews.com/health/even-drink-day-boosts-cancer-death-risk-alcohol-study-finds-1C8381639?franchiseSlug=healthmain

“Drinking linked to endometrial cancer risk”  http://www.nbcnews.com/id/20889546/ns/health-cancer/t/drinking-linked-endometrial-cancer-risk/

“Does drinking alcohol increase the risk of cancer? Overall, alcohol consumption is one of the top 10 contributors to sickness and death from injuries, motor vehicle crashes, homicides and suicides, sexual assaults, sexually transmitted infections from unsafe sex, falls, birth defects, depression, disorders of the gastrointestinal tract, and sleep disorders. Additionally, there is a lot of evidence that drinking alcohol increases the risk of several cancers.”  http://www.cancer.org/cancer/news/expertvoices/post/2013/06/26/does-drinking-alcohol-increase-the-risk-of-cancer.aspx

“Alcohol and Breast Cancer Risk: New Findings… Epidemiological studies have consistently found that heavy drinking can increase the risk of liver, head and neck, and esophageal cancers, and even moderate drinking has been shown to increase the risk of breast cancer.”  http://www.cancer.gov/cancertopics/causes/breast/alcoholuse0408

“Marijuana… Cannabis sativais an annual plant that grows wild in warm and tropical climates throughout the world and is cultivated commercially. The leaves and buds of the plant have been used in herbal remedies for centuries… As of 2012, there are reports online suggesting that marijuana oil or “hemp” oil can cure cancer, as well as diabetes, ulcers, arthritis, migraines, insomnia, infections, and many other diseases.” http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/herbsvitaminsandminerals/marijuana

Alcohol causes cancer, and here’s the evidence:

Alcohol causes at least seven types of cancer
 

“Alcohol causes cancer, and here’s the evidence… Many of us are aware of the short-term effects of drinking too much – feeling sick, a hangover, a spot of embarrassment, a vague but hard-to-pin-down sense of guilt – but the long-term effects often slip under the radar. These include a higher risk of many cancers, heart disease, stroke and more.”   http://scienceblog.cancerresearchuk.org/2010/01/28/alcohol-and-cancer-the-evidence/   

“ALCOHOL AND CANCER… Epidemiological data have identified chronic alcohol consumption as a significant risk factor for upper alimentary tract cancer, including cancer of the oropharynx, larynx and the oesophagus and of the liver.” http://alcalc.oxfordjournals.org/content/39/3/155.long

“Molecular mechanisms of alcohol-mediated carcinogenesis… Although the mechanisms for alcohol-associated carcinogenesis are not completely understood, most recent research has focused on acetaldehyde, the first and most toxic ethanol metabolite, as a cancer-causing agent. Ethanol may also stimulate carcinogenesis… Alcohol-related carcinogenesis may interact with other factors such as smoking, diet and comorbidities, and depends on genetic susceptibility.” http://www.ncbi.nlm.nih.gov/pubmed/17646865

“Liver cancer and alcohol… Based on the association of alcohol with cancer, a International Agency for Research on Cancer working group recently deemed alcoholic beverages “carcinogenic to humans,” causally related to occurrence of malignant tumors of the oral cavity, pharynx, larynx, esophagus, liver, colorectum, and female breast.”  http://www.ncbi.nlm.nih.gov/pubmed/23101985

“Alcohol and pancreatic cancer… heavy alcohol consumption has been known to be a major cause of chronic pancreatitis and a risk factor for type 2 diabetes mellitus, both of which are linked to pancreatic cancer.”  http://www.ncbi.nlm.nih.gov/pubmed/16054982

“Alcohol drinking and colorectal cancer risk: an overall and dose–response meta-analysis of published studies… The International Agency for Research on Cancer (IARC) concluded that alcohol consumption is related to colorectal cancer (CRC)… This meta-analysis provides strong evidence for an association between alcohol drinking of >1 drink/day and colorectal cancer risk.”  http://annonc.oxfordjournals.org/content/22/9/1958.long

“Alcohol consumption and the risk of breast cancer… Epidemiologic studies addressing the association of alcohol consumption with breast cancer consistently suggest a modest association and a dose-response relationship… Data from a variety of epidemiologic studies suggest that chronic alcohol consumption even in moderate amounts increases a woman’s risk for breast cancer… Epidemiologic data further suggest that consumption of larger amounts of alcohol is associated with a higher risk of breast cancer…  Avoiding overconsumption of alcohol is recommended, especially for women with known risk factors for breast cancer.”  http://www.scielosp.org/scielo.php?script=sci_arttext&pid=S0036-36342011000500012&lng=en&nrm=iso&tlng=en 

“Alcohol consumption and digestive tract cancer…  data indicating that alcohol is an important factor increasing the risk to develop gastrointestinal cancer are consolidating… Functional genetic variants of alcohol-metabolizing enzymes proved to be associated with increased risk for esophageal and gastric cancer… Alcohol overconsumption is a serious avoidable risk factor for the development of gastrointestinal tract cancer, both alone but even more in combination with other risk factors such as tobacco and obesity.”  http://www.ncbi.nlm.nih.gov/pubmed/22797570

“Cancer stem cells generated by alcohol, diabetes, and HCV”  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306127/

“Epidemiology and Pathophysiology of Alcohol and Breast Cancer: Update 2012… Alcohol consumption is a risk factor for cancer of various organs including the upper alimentary tract, the liver, the colorectum and the female breast… Women should not exceed one drink/day, and women at elevated risk for breast cancer should avoid alcohol or consume alcohol occasionally only.”  http://alcalc.oxfordjournals.org/content/47/3/204.long

“Human carcinogenesis and alcohol in hepato-gastroenterology… Alcohol consumption is one of the top-10 risks for worldwide burden of disease. The International Agency for Research for Cancer affirmed that there was evidence for the carcinogenicity of ethanol in animals and classified alcohol consumption as carcinogenic for humans. Alcohol consumption causes cancers of the oral cavity, pharynx, larynx, oesophagus, colorectum, liver, pancreas and female breast…”  http://www.ncbi.nlm.nih.gov/pubmed/22696879 

“The Burden of Cancer Attributable to Alcohol Consumption… All types of alcoholic beverages are associated with an increased risk which suggests that ethanol itself is the crucial compound which causes that effect… In our opinion, there are not enough data to support the actually safe intake of alcohol. Any level of alcohol consumption increase the risk of developing an alcohol related cancer.”  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391950/ 

“Tobacco smoking, alcohol drinking and risk of oral cavity cancer by subsite: results of a French population-based case-control study, the ICARE study…  Tobacco smoking increased the risk of oral cavity cancer even for the smaller quantities and durations, whereas alcohol drinking increased this risk only in heavy drinkers who were also ever smokers. The combined effect of smoking and drinking was greater than multiplicative…”  http://www.ncbi.nlm.nih.gov/pubmed/22976386

“Alcohol-Attributable Cancer Deaths and Years of Potential Life Lost in the United States. Objectives: Our goal was to provide current estimates of alcohol-attributable cancer mortality and years of potential life lost (YPLL) in the United States. Results: Alcohol consumption resulted in an estimated 18,200 to 21,300 cancer deaths, or 3.2% to 3.7% of all US cancer deaths. Conclusions: Alcohol remains a major contributor to cancer mortality and YPLL. Higher consumption increases risk but there is no safe threshold for alcohol and cancer risk. Reducing alcohol consumption is an important and underemphasized cancer prevention strategy.”  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673233/

“Ethanol-mediated promotion of oesophageal carcinogenesis: association with lipid peroxidation and changes in phospholipid fatty acid profile of the target tissue… Ethanol consumption is a high risk factor for oesophageal carcinoma…  ethanol may promote carcinogenesis through excessive cell proliferation…”  http://www.ncbi.nlm.nih.gov/pubmed/9199722

“Ethanol-mediated carcinogenesis in the human esophagus implicates CYP2E1 induction and the generation of carcinogenic DNA-lesions… Chronic alcohol consumption is a major risk factor for esophageal cancer… Ethanol exerts its carcinogenic effect in the liver among others via the induction of cytochrome P450 2E1 (CYP2E1) and the generation of carcinogenic etheno-DNA adducts…” http://www.ncbi.nlm.nih.gov/pubmed/20715111

“Ethanol enhances tumor angiogenesis in vitro induced by low-dose arsenic in colon cancer cells through hypoxia-inducible factor 1 alpha pathway… Arsenic has been known to induce carcinogenesis and enhance tumor development via complex and unclear mechanism. Ethanol is also a well-established risk factor for many malignancies…We conclude that ethanol is able to enhance arsenic-induced tumor angiogenesis in colorectal cancer cells…”  http://www.ncbi.nlm.nih.gov/pubmed/22872060

“Ethanol-induced mast cell-mediated inflammation leads to increased susceptibility of intestinal tumorigenesis in the APC Δ468 min mouse model of colon cancer… Chronic and frequent alcohol (ethanol [EtOH]) intake has been associated with an increased incidence of several types of cancers including breast, mouth, throat, esophageal, stomach, and colorectal (CRC). The underlying mechanism of this deleterious carcinogenic effect of alcohol has not been clearly established… Our data show that chronic alcohol intake promotes: (i) intestinal tumorigenesis and tumor invasion in genetically susceptible mice; (ii) increases in polyp-associated mast cells; and (iii) mast cell-mediated tumor migration in vitro. Both our in vivo and in vitro studies suggest that mast cell-mediated inflammation could be 1 mechanism by which alcohol promotes carcinogenesis.”  http://www.ncbi.nlm.nih.gov/pubmed/23320800

“Ethanol Promotes Chemically Induced Oral Cancer in Mice through Activation of the 5-Lipoxygenase Pathway of Arachidonic Acid Metabolism… Alcohol drinking is a known risk factor for oral cancer in humans… this study clearly demonstrated that ethanol promoted 4NQO-induced oral carcinogenesis…”  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208736/

“Ethanol Disrupts Vascular Endothelial Barrier: Implication in Cancer Metastasis… ethanol exposure enhances tumor progression. Ethanol exposure promotes cancer cell invasion and is implicated in tumor metastasis…Our results indicate that ethanol may facilitate cancer metastasis by disrupting the vascular endothelial barrier.”  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327869/

“Ethanol Promotes Mammary Tumor Growth and Angiogenesis: the Involvement of Chemoattractant Factor MCP-1… Alcohol consumption is a risk factor for breast cancer in humans. Experimental studies indicate that alcohol exposure promotes malignant progression of mammary tumors… Ethanol promotes mammary tumor growth and metastasis… A causal role was recently attributed to inflammation in many malignant diseases, including breast cancer… It has been demonstrated that alcohol induces pro-inflammatory mediators, and enhanced inflammation may underlie many diseases or disorders caused by alcohol abuse…”  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323664/

“Alcohol drinking, consumption patterns and breast cancer among Danish nurses: a cohort study… these data suggest, that weekly alcohol consumption increases the risk of breast cancer in women reporting alcohol consumption above the average for women in general. The risk is minor for moderate levels of weekly alcohol intake, but increases for each extra drink consumed. Weekend consumption and binge drinking seem to be related to an additional increased risk of breast cancer.”  http://eurpub.oxfordjournals.org/content/17/6/624.long

“Alcohol intake, type of beverage, and risk of breast cancer in pre- and postmenopausal women… Most studies of the relation between alcohol consumption and breast cancer have shown a modestly increased risk… CONCLUSIONS: Total alcohol intake of more than 27 drinks per week increases breast cancer risk in premenopausal women independently of the type of alcohol. Among postmenopausal women, an intake of spirits of more than six drinks per week increases breast cancer risk.”  http://www.ncbi.nlm.nih.gov/pubmed/15252295

“Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk… Relative risks of developing invasive breast cancer… Low levels of alcohol consumption were associated with a small increase in breast cancer risk, with the most consistent measure being cumulative alcohol intake throughout adult life. Alcohol intake both earlier and later in adult life was independently associated with risk… higher consumption of alcohol has been associated with an increased risk of breast cancer…”  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292347/

“Moderate alcohol consumption and breast cancer in women: from epidemiology to mechanisms and interventions… Epidemiologic studies indicate that moderate alcohol consumption increases breast cancer risk in women… In this commentary, we focus on some recent epidemiologic studies linking moderate alcohol consumption to breast cancer risk and place the results of those studies within the framework of our current understanding of the temporal and mechanistic basis of human carcinogenesis. This analysis supports the hypothesis that alcohol acts as a weak cumulative breast carcinogen and may also be a tumor promoter.”  http://www.ncbi.nlm.nih.gov/pubmed/23072454

“Light alcohol drinking and cancer: a meta-analysis… There is convincing evidence that alcohol consumption increases the risk of cancer… We evaluated the association between light drinking and cancer of the colorectum, breast, larynx, liver, esophagus, oral cavity and pharynx… CONCLUSIONS: Light drinking increases the risk of cancer of oral cavity and pharynx, esophagus and female breast.”  http://www.ncbi.nlm.nih.gov/pubmed/22910838

“Alcohol-related diseases and carcinogenesis…  Data are presented demonstrating the induction, by chronic ethanol consumption, of microsomal enzymes which convert procarcinogens to carcinogens… The hypothesis is presented that ethanol-mediated induction of enzyme systems which activate procarcinogens to carcinogens in various tissues contributes to the enhanced incidence of cancer in the alcoholic.”  http://www.ncbi.nlm.nih.gov/pubmed/221110

“The Role of Cytochrome P450 2E1 in Ethanol-Mediated Carcinogenesis… there is increasing evidence that CYP2E1 induced by chronic alcohol consumption plays an important role in alcohol mediated carcinogenesis.”  http://www.ncbi.nlm.nih.gov/pubmed/23400919 

Role of cannabinoid CB2 receptor in the reinforcing actions of ethanol.

“This study examines the role of the cannabinoid CB2 receptor (CB2 r) on the vulnerability to ethanol consumption… These results suggest that deletion of the CB2 r gene increased preference for and vulnerability to ethanol consumption…

Future studies will determine the role of CB2 r as a target for the treatment of problems related with alcohol consumption.”

http://www.ncbi.nlm.nih.gov/pubmed/23855434

Alcohol Not Marijuana Triggers Drug Abuse in Teenagers

“If you want your kids to stay away from drugs, then you might want to keep teenagers off alcohol because a new study says that long term drug abuse is likely to occur due to alcohol, not marijuana, use.

Researchers analyzed the data to find out what substances were being tried by students. They checked for use of marijuana, cocaine, heroin, LSD, amphetamines, tranquilizers and other narcotics.

Alcohol was the first substance to be tried by students, the results showed.

“By recognizing the important predictive role of alcohol and delaying initiation of alcohol use, school officials and public health leaders can positively impact the progression of substance use. I am confident in our findings and the clear implications they have for school-based prevention programs. By delaying and/or preventing the use of alcohol, these programs can indirectly reduce the rate of use of other substances,” Adam Barry, an assistant professor and researcher in the College of Health and Human Performance at the University of Florida.

“These findings add further credence to the literature identifying alcohol as the gateway drug to other substance use,” Barry said.”

Read more: http://www.medicaldaily.com/articles/10771/20120711/alcohol-addiction-marijuana-drugs.htm

[The role of the cannabinoid system in the pathogenesis and treatment of alcohol dependence].

Abstract

“The lack of satisfactory results of alcohol dependence treatment force us to search for new directions of research. Recent studies concentrate on endocannabinoid transmission. The results show an interplay between the endocannabinoid and dopaminergic signaling in activation of the limbic reward system. The mechanisms leading to development of dependence are very complex and poorly recognized. Endogenous cannabinoids seem to have an important role in the functioning of this system, both directly and indirectly affecting the level of different neurotransmitters. The effect of alcohol on the endocannabinoid system is also complex and involves changes at the molecular level. Experimental studies have demonstrated an important role of the CB1 receptors in the neurochemical mechanism of alcohol consumption and its regulation. SR141716 (rimonabant), a CB1 receptor antagonist, significantly lowers voluntary alcohol intake and motivation for its consumption in various experimental studies. Very encouraging results of preclinical studies were not completely confirmed in the clinical studies. However, further clinical studies are still necessary.”

http://www.ncbi.nlm.nih.gov/pubmed/21934185

ROLE OF THE ENDOCANNABINOID SYSTEM IN THE DEVELOPMENT OF TOLERANCE TO ALCOHOL

“Alcohol dependence is a leading cause of morbidity and various medical and socio-economic problems. It is defined by compulsive, excessive use of alcohol despite negative consequences. Alcohol dependence is usually accompanied by tolerance to the intoxicating effects of alcohol and by withdrawal symptoms including tremors and confusion when consumption of alcohol ceases. Although important advances have been made in recent years in understanding the mechanisms underlying the development of tolerance to and dependence on alcohol, the exact mechanisms are still elusive. The present article reviews the role played by the endocannabinoid system in the molecular mechanism involved in the development of alcohol tolerance, which possibly influences alcohol-drinking behaviour.”

“The present review evaluates the evidence that the endocannabinoid system plays in the development of tolerance to alcohol. The identification of a G-protein-coupled receptor, namely, the cannabinoid receptor (CB1 receptor), which was activated by Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive component of marijuana, led to the discovery of endogenous cannabinoid agonists. Until now, four fatty acid derivatives identified to be arachidonylethanolamide (AEA), 2-arachidonylglycerol (2-AG), 2-arachidonylglycerol ether (noladin ether) and virodhamine have been isolated from both nervous and peripheral tissues. Both AEA and 2-AG have been shown to mimic the pharmacological and behavioural effects of Δ9-THC. The role of the endocannabinoid system in the development of tolerance to alcohol was not known until recently. Recent studies from our laboratory have implicated for the first time a role for the endocannabinoid system in development of tolerance to alcohol. Chronic alcohol treatment has been shown to down-regulate CB1 receptors and its signal transduction. The observed downregulation of CB1 receptor function results from the persistent stimulation of the receptors by AEA and 2-AG, the synthesis of which has been shown to be increased by chronic alcohol treatment. The enhanced formation of endocannabinoids may subsequently influence the release of neurotransmitters. It was found that the DBA/2 mice, known to avoid alcohol intake, have significantly reduced CB1 receptor function in the brain, consistent with other studies in which the CB1 receptor antagonist SR 141716A has been shown to block voluntary alcohol intake in rodents. Similarly, activation of the CB1 receptor system promoted alcohol craving, suggesting a role for the CB1 receptor gene in excessive alcohol drinking behaviour and development of alcoholism. Ongoing investigations may lead to a better understanding of the mechanisms underlying the development of tolerance to alcohol and to develop therapeutic strategies to treat alcoholism.”

“CONCLUSION

Over the past seven years, remarkable advances have been made towards our understanding of the role played by the endocannabinoid system in the development of alcohol tolerance and alcohol-drinking behaviour. These studies have provided strong evidence that CB1 receptors and the endocannabinoid system serve as an attractive therapeutic target for the treatment of alcohol tolerance and alcohol-related disorders. The data reviewed here provide convincing evidence that alcohol tolerance involves the downregulation of the CB1 receptor and its function. The observed neuro-adaptation may be due to increased accumulation of the endocannabinoids AEA and 2-AG. Treatment with the CB1 receptor antagonist SR 141716A led to reduced consumption of alcohol in rodents and activation of the same endogenous cannabinoid systems by the CB1 receptor agonist promoted alcohol craving, which may be related to the change in the levels of dopamine in the NAc. Further, reduced alcohol intake by the CB1 receptor knockout mice is consistent with our previous observation that significantly lower levels of functional CB1 receptors are found in the alcohol-avoiding DBA/2 mouse strain compared with the alcohol-preferring C57BL/6 mouse strain. These observations suggest the involvement of the CB1 receptors in controlling voluntary alcohol consumption and the involvement of the endocannabinoid system in the development of alcohol tolerance. However, further studies are necessary to unfold the exact mechanism by which alcohol exerts its pharmacological and behavioural effects through the endocannabinoid system. The investigation of the detailed signalling cascade for the actions of both endocannabinoids and CB1 receptors will be of great value in understanding their physiological and functional role in several neurological disorders, voluntary alcohol intake and alcohol craving, including the behavioural neuroadaptation to alcohol. Such studies may also lead to the development of endocannabinoid signalling-targeted drugs, which may help to reduce both alcohol intake and alcohol craving. These results suggest that the cannabinoid antagonist, SR 141716A, may be useful as a potential therapeutic agent in alcohol dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/15550443

http://alcalc.oxfordjournals.org/content/40/1/15.long

The endocannabinoid signaling system: a potential target for next-generation therapeutics for alcoholism

“Alcoholism is a complex disorder affecting modern society in many ways, yet there are few effective treatment strategies currently available.”

“Research into the endocannabinoid signaling system has grown exponentially in recent years following the discovery of cannabinoid receptors (CB) and their endogenous ligands, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Important advances have been made in our understanding of the endocannabinoid signaling system in various aspects of alcoholism, including alcohol-seeking behavior. Alcohol increases the synthesis or impairs the degradation of endocannabinoids, leading to a locally elevated endocannabinoid tone within the brain. Elevated endocannabinoid tone might be expected to result in compensatory down-regulation of CB1 receptors or dampened signal transduction. Following release, endocannabinoids diffuse back to the presynaptic neuron where they act as short-range modulators of synaptic activity by altering neurotransmitter release and synaptic plasticity. Mice treated with the CB1 receptor antagonist SR141716A (rimonabant) or homozygous for a deletion of the CB1 receptor gene exhibit reduced voluntary alcohol intake. CB1 knockout mice also show increased alcohol sensitivity, withdrawal, and reduced conditioned place preference. Conversely, activation of CB1 receptor promotes alcohol intake. Recent studies also suggest that elevated endocannabinoid tone due to impaired degradation contributes to high alcohol preference and self-administration. These effects are reversed by local administration of rimonabant, suggesting the participation of the endocannabinoid signaling system in high alcohol preference and self-administration. These recent advances will be reviewed with an emphasis on the endocannabinoid signaling system for possible therapeutic interventions of alcoholism.”

“Overwhelmingly, recent studies suggest that cannabinoids and alcohol activate similar reward pathways. The CB1 receptors also seem to regulate the reinforcing properties of alcohol. The discovery of cannabinoid receptors and their endogenous ligands set a landmark in cannabinoid research. These discoveries impacted significantly on alcohol research, too, since there is now considerable evidence that endocannabinoid signaling plays a key role in alcohol addiction, and this has promising clinical consequences. The purpose of this article is to analyze the interaction between alcohol and endocannabinoid signaling, paying particular attention to the reward mechanism. Therapeutic aspects driving from these new insights are also discussed.”

“THERAPEUTIC OPPORTUNITY”

“Although the detailed physiology, biochemistry and pathophysiology of the endocannabinoid signaling system have not been fully investigated, there is already overwhelming evidence to indicate that pharmacological modulation of the endocannabinoid signaling system could provide new treatments for a number of disease states, including alcohol addiction. Recently it was reported that rimonabant holds an important therapeutic role in treating liver fibrosis and alcohol abuse accounts for more than half of the prevalence of liver fibrosis and cirrhosis in the western world. Therefore, it is important to examine whether alcohol-induced liver fibrosis and cirrhosis results in increased endocannabinoid levels and rimonabant reverses alcohol-induced liver fibrosis/cirrhosis. In terms of drug development, the CB1 receptor antagonist rimonabant has progressed furthest and is in late phase III trials for the treatment of obesity and as an aid for smoking cessation. An NIAAA clinical study of the effectiveness of rimonabant to reduce voluntary alcohol drinking has progressed to phase I trials. Pending results of the clinical trials, rimonabant could become an important addition to the limited arsenal of effective treatments for alcoholism. During drug abuse there are changes in endocannabinoid levels in various brain regions. Therefore, drugs which regulate the level of endocannabinoids by inhibiting their metabolism (FAAH inhibitors such as URB597) or uptake (AM404) could locally target sites while limiting effects in uninvolved cognitive areas to produce a higher therapeutic value. Cannabinoid interactions with the dopamine system have been offered as a possible mechanism for some of the therapeutic potential of cannabinoid-based drugs in alcoholism. A recent study provides evidence of the ability of CB1 receptor antagonist to mitigate alcohol-withdrawal symptoms, and block the formation of physical dependency by inhibiting alcohol intake. Recent data on the role of CB1 receptors in alcohol drinking behavior, including alcohol tolerance as discussed in the earlier sections, clearly suggest that agents such as CB1 receptor antagonists, including rimonabant, will be promising therapeutic agents for the treatment of alcoholism.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1975858/

A review of the interactions between alcohol and the endocannabinoid system: implications for alcohol dependence and future directions for research.

Abstract

“Over the past fifty years a significant body of evidence has been compiled suggesting an interaction between the endocannabinoid (EC) system and alcohol dependence. However, much of this work has been conducted only in the past two decades following the elucidation of the molecular constituents of the EC system that began with the serendipitous discovery of the cannabinoid 1 receptor (CB1). Since then, novel pharmacological and genetic tools have enabled researchers to manipulate select components of the EC system, to determine their contribution to the motivation to consume ethanol. From these preclinical studies, it is evident that CB1 contributes the motivational and reinforcing properties of ethanol, and chronic consumption of ethanol alters EC transmitter levels and CB1 expression in brain nuclei associated with addiction pathways. These results are augmented by in vitro and ex vivo studies showing that acute and chronic treatment with ethanol produces physiologically relevant alterations in the function of the EC system. This report provides a current and comprehensive review of the literature regarding the interactions between ethanol and the EC system. We begin be reviewing the studies published prior to the discovery of the EC system that compared the behavioral and physiological effects of cannabinoids with ethanol in addition to cross-tolerance between these drugs. Next, a brief overview of the molecular constituents of the EC system is provided as context for the subsequent review of more recent studies examining the interaction of ethanol with the EC system. These results are compiled into a summary providing a scheme for the known changes to the components of the EC system in different stages of alcohol dependence. Finally, future directions for research are discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/22459871

Functional interactions between endogenous cannabinoid and opioid systems: focus on alcohol, genetics and drug-addicted behaviors.

Abstract

“Although the first studies regarding the endogenous opioid system and addiction were published during the 1940s, addiction and cannabinoids were not addressed until the 1970s. Currently, the number of opioid addiction studies indexed in PubMed-Medline is 16 times greater than the number of cannabinoid addiction reports. More recently, functional interactions have been demonstrated between the endogenous cannabinoid and opioid systems. For example, the cannabinoid brain receptor type 1 (CB1) and mu opioid receptor type 1 (MOR1) co-localize in the same presynaptic nerve terminals and signal through a common receptor-mediated G-protein pathway. Here, we review a great variety of behavioral models of drug addiction and alcohol-related behaviors. We also include data providing clear evidence that activation of the cannabinoid and opioid endogenous systems via WIN 55,512-2 (0.4-10 mg/kg) and morphine (1.0-10 mg/kg), respectively, produces similar levels of relapse to alcohol in operant alcohol self-administration tasks. Finally, we discuss genetic studies that reveal significant associations between polymorphisms in MOR1 and CB1 receptors and drug addiction. For example, the SNP A118G, which changes the amino acid aspartate to asparagine in the MOR1 gene, is highly associated with altered opioid system function. The presence of a microsatellite polymorphism of an (AAT)n triplet near the CB1 gene is associated with drug addiction phenotypes. But, studies exploring haplotypes with regard to both systems, however, are lacking.”

http://www.ncbi.nlm.nih.gov/pubmed/20196742cannabinoid op