Cannabinoid-blocking Weight-loss Drug Might Fight Alcoholic Fatty Liver

March 6, 2008

Science Daily/Cell Press

The cannabinoid receptors best known for delivering the psychological effects of marijuana also explain the connection between chronic alcohol use and a buildup of fat in the liver, according to a report in the March issue of Cell Metabolism. Alcoholic fatty liver can progress to more serious disease, and alcoholism is a leading cause of liver disease in Western societies.

The researchers also found that mice treated with rimonabant, a drug designed to block cannabinoid receptors, become resistant to alcohol's fat-building effects in the liver. Rimonabant is now in use for weight loss in several European countries but has not received FDA approval for use in the United States.

"What makes these findings particularly interesting from our perspective is that they may have practical implications," said George Kunos of the National Institute on Alcohol Abuse and Alcoholism. "Treatment of animals with a [cannabinoid receptor] antagonist largely prevented alcohol's effect. It suggests that the development of fatty liver in those who use alcohol could be interfered with, or perhaps reversed, with such treatment."

In addition to alcoholism, obesity can also lead to the development of fatty liver disease. Scientists have shown that natural cannabinoids, so-called endocannabinoids, and CB1 cannabinoid receptors in the livers of mice are increased when animals are fed a high-fat diet. Studies have also shown that mice lacking CB1 receptors and mice treated with drugs that block these receptors are protected from obesity and fatty liver.

"Similar to high-fat diet, chronic ethanol exposure can increase endocannabinoid levels, at least in the brain," the researchers said. The apparent similarities between diet- and ethanol-induced changes in fat metabolism and endocannabinoid activity in the liver suggested that endocannabinoids might also be a culprit in ethanol-induced fatty liver.

Kunos's team now shows that mice fed a low-fat diet and ethanol show an increase in the gene encoding the CB1 receptor and in liver levels of one endocannabinoid, 2-arachidonoylglycerol (2-AG). These mice also developed fatty livers. In contrast, the livers of mice fed the ethanol diet plus rimonabant did not differ in fat content from those of mice fed a control diet. Similarly, mice lacking CB1 receptors, either throughout the body or only in the liver, gained protection from alcoholic fatty liver.

"Although alcoholic fatty liver is reversible in its early stages by cessation of drinking, this is often not feasible," the researchers concluded. "The present findings suggest that treatment with a CB1 antagonist may slow the development of fatty liver and thus prevent or delay its progression to more severe and irreversible forms of liver disease."

Drugs designed to selectively act on CB1 receptors found outside of the brain might fight fatty liver with less risk of adverse side effects, including anxiety and depression, they added. "Rimonabant has recently been introduced in Europe for the treatment of visceral obesity and the metabolic syndrome, which themselves are known risk factors for [liver disease]. Clinical trials testing the effectiveness of CB1 receptor blockers in the treatment of both alcoholic and nonalcoholic fatty liver and their more severe sequelae may be warranted."

https://www.sciencedaily.com/releases/2008/03/080304124345.htm

Role of Cannabinoid Receptors in Alcohol Abuse Examined

September 11, 2005

Science Daily/Brookhaven National Laboratory

A new set of experiments in mice confirms that a brain receptor associated with the reinforcing effects of marijuana also helps to stimulate the rewarding and pleasurable effects of alcohol.

The research, which was conducted at the U.S. Department of Energy’s Brookhaven National Laboratory and was published online September 2, 2005 by the journal Behavioural Brain Research, confirms a genetic basis for susceptibility to alcohol abuse and also suggests that drugs designed to block these receptors could be useful in treatment.

“These findings build on our understanding of how various receptors in the brain’s reward circuits contribute to alcohol abuse, help us understand the role of genetic susceptibility, and move us farther along the path toward successful treatments,” said Brookhaven’s Panayotis (Peter) Thanos, lead author of this study and many others on “reward” receptors and drinking.

Earlier studies in animals and humans have suggested that so-called cannabinoid receptors known as CB1 — which are directly involved in triggering the reinforcing properties of marijuana — might also stimulate reward pathways in response to drinking alcohol. Thanos’ group investigated this association in two experiments.

In the first experiment, they measured alcohol preference and intake in mice with different levels of CB1 receptors: wild type mice with normal levels of CB1; heterozygous mice with approximately 50 percent levels; and so-called knockout (KO) mice that lack the gene for CB1 and therefore have no CB1 receptors. All mice were given a choice of two drinking bottles, one with pure water and one with a 10 percent alcohol solution — approximately equivalent to the alcohol content of wine. Mice with the normal levels of CB1 receptors had a stronger preference for alcohol and drank more than the other two groups, with the CB1-deficient mice showing the lowest alcohol consumption.

After establishing each group’s level of drinking, the scientists treated animals with a drug known to block CB1 receptors (SR141716A) and tested them again. (These animals were also compared with animals injected with plain saline to control for the effect of the injection.) In response to the CB1 receptor-blocking drug, mice with normal and intermediate levels of receptors drank significantly less alcohol compared to their pre-treatment levels, while KO mice showed no change in drinking in response to the treatment.

In the second experiment, the scientists compared the tendency of wild type and KO mice to seek out an environment in which they had previously been given alcohol. Known as “conditioned place preference,” this is an established technique for determining an animal’s preference for a drug.

Animals were first conditioned to “expect” alcohol in a given portion of a three-chambered cage while being given an injection of saline in the opposite end, and then monitored for how much time they spent in the alcohol chamber “seeking” the drug. Wild type animals, with normal levels of CB1, spent more time in the alcohol-associated chamber than the saline chamber, showing a decided preference, while KO mice (with no CB1 receptors) showed no significant preference for one chamber over the other.

“These results support our belief that the cannabinoid system and CB1 receptors play a critical role in mediating the rewarding and pleasurable properties of alcohol, contributing to alcohol dependency and abuse,” Thanos said.

In addition, the fact that the mice with intermediate levels of CB1 exhibited alcohol preference and intake midway between those with high levels of receptors and those with none suggests that the genetic difference between strains quantitatively influences the preference for and the amount of alcohol consumed. “These results provide further evidence for a genetic component to alcohol abuse that includes the CB1 gene — the same gene that is important for the behavioral effects of marijuana,” Thanos said.

While it remains unclear exactly how CB1 triggers the rewarding effects of alcohol, one possibility is that activation of the CB1 receptor somehow blocks the brain’s normal “stop” signals for the production of dopamine, another brain chemical known to play a role in addiction. Without the stop signal, more dopamine is released to produce a pleasure/reward response.

Since blockade of the CB1 receptor with SR141716A appears to effectively reduce alcohol intake and preference, this study also suggests that such CB1 receptor-blocking drugs might play an important role in the future treatment of alcohol abuse.

This study was funded by the Office of Biological and Environmental Research within the U.S. Department of Energy’s (DOE) Office of Science; by the National Institute on Drug Abuse and the Intramural Research Program of the NIH, [National Institute on Alcohol Abuse and Alcoholism]. The DOE has a long-standing interest in research on addiction that builds, as this study does, on the knowledge of brain receptors gained through brain-imaging studies. Brain-imaging techniques such as MRI and PET are a direct outgrowth of DOE’s support of basic physics research.

https://www.sciencedaily.com/releases/2005/09/050908084256.htm

Mouse Model Links Alcohol Intake to Marijuana-like Brain Compounds

January 21, 2003

Science Daily/NIH/National Institute On Alcohol Abuse And Alcoholism

Brain molecules similar to the active compound in marijuana help to regulate alcohol consumption, according to new reports by scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, Maryland, and a separate NIAAA-supported group at several New York state research institutions.

In studies conducted with a strain of mice known to have a high preference for alcohol, the scientists found greatly reduced alcohol intake in mice specially bred to lack CB1, the brain receptor for innate marijuana-like substances known as endocannabinoids. The effect was age dependent, the Bethesda group found. The New York scientists showed that the endocannabinoid system activates a brain region known as the nucleus accumbens, which plays a major role in mediating the rewarding effects of alcohol. Both groups had shown that alcohol intake among normal mice of the same alcohol-preferring strain could be reduced by treating the animals with a drug that blocks CB1 receptors in the brain.

The new reports appear in the early online versions of the Proceedings of the National Academy of Sciences, Volume 20, Number 3, at www.pnas.org and the Journal of Neurochemistry, Volume 24, Number 4, at www.blackwell-synergy.com/servlet/useragent?func=showIssues&code=jnc in the week beginning January 20, 2003 (specific dates to be determined).

"These are important findings," notes NIAAA Director Ting-Kai Li, M.D. "Implicating yet another neurochemical mechanism in alcohol consumption opens another potential avenue for the development of new pharmacologic agents to prevent and treat alcohol problems."

The brain's multiple communication pathways employ a wide variety of signaling molecules known as neurotransmitters to relay messages from one brain cell to another. Researchers have found that alcohol affects numerous neurotransmitters and that a variety of brain pathways are involved in alcohol abuse and dependence. Determining precisely how alcohol interacts with brain cells and affects brain chemistry is an ongoing focus of research. Knowledge gained through this research helps scientists develop drugs to diminish the desire to consume alcohol and to counteract alcohol's effects.

Since their discovery in the early 1990's, endocannabinoids and endocannabinoid receptors have been studied intensely by alcohol and drug abuse researchers. Recent animal studies have suggested that the so-called "endocannabinoid system" is involved in some of the pharmacologic effects of alcohol and in drinking behavior.

In one of the current studies, researchers led by George Kunos, M.D., Ph.D., Scientific Director of NIAAA's Division of Intramural Biological and Clinical Research, found that, among the normal, alcohol-preferring mice–that is, those with intact CB1 receptors–the animals' appetite for both alcohol and food decreased with age. This occurred even though levels of endocannabinoids and the density of CB1 receptors were found to be similar in the brains of young and old mice.

"Although unexpected," says Dr. Kunos, "the observed age-dependent decline in alcohol preference in mice parallels observations in humans, in that only some teenage binge drinkers become alcoholics as adults, and that the onset of alcoholism declines with age."

The researchers found a possible explanation for this phenomenon by comparing the efficiency of the signal sent by the CB1 receptors in different regions of the brain in young and old mice. In old mice, they found diminished CB1 signaling in an area known as the limbic forebrain. The part of the limbic forebrain known as the nucleus accumbens plays a major role in mediating the rewarding properties of alcohol and cannabinoids and also is thought to help regulate appetite. The nucleus accumbens exerts its effects through the release of the neurotransmitter dopamine. Alcohol ingestion typically elicits a robust release of dopamine from the nucleus accumbens.

The second report by NIAAA-supported scientists led by Basalingappa L. Hungund, Ph.D., of the New York State Psychiatric Institute and Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York, complements the findings of the Kunos research team. Dr. Hungund and colleagues found that, in addition to showing a dramatic reduction in alcohol intake, alcohol-preferring mice that lack CB1 receptors release no dopamine from the nucleus accumbens after they drink alcohol. In mice with intact CB1 receptors, the researchers were able to abolish alcohol-induced release of dopamine from the nucleus accumbens by treating the animals with a drug that blocks CB1 receptors.

"Our results," says coauthor Balapal Basavarajappa, Ph.D., "clearly suggest that the CB1 receptor system is involved in ethanol-induced dopamine release in the nucleus accumbens and indicate that activation of the limbic dopamine system is required for the reinforcing effects of alcohol. They further suggest an interaction between the cannabinoidergic and dopaminergic systems in the reinforcing properties of drugs of abuse, including alcohol."

"Taken together," adds Dr. Kunos, "these findings provide unequivocal evidence for the role of endocannabinoids and CB1 in alcohol drinking behavior in rodents, and suggest that the CB1 receptor may be a promising pharmacotherapy target."

The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of U.S. research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA disseminates research findings to scientists, practitioners, policy makers, and the general public.

https://www.sciencedaily.com/releases/2003/01/030121080758.htm