Date: October 11, 2007

Speaker's Name, Affiliation:

Michael Lewis
Hunter, CUNY

Seminar Title:"Alcohol Dependence: Feeding, nutrition, and reinforcement mechanisms"

Presiding Chair: Harry R. Kissileff, Ph.D. (Allan Geleibter, Ph.D. was the chair, in place of Harry Kissileff)

Rapporteur: Kathleen L. Keller, Ph.D.

Attendees and their Affiliation:

Kathleen Keller	Columbia/Obesity Research Center
Allan Geleibter	Obesity Research Center
Amy Samuelson	GSK
Rhoda Gruen	Columbia
Marie Ines Velazeo	Firmenich
Christian Margot	Firmenich
Nicole Avena	Rockefeller
Bart Hoebel	Princeton
Dara Bellace	Cornell
Susan Carnell	ORC
Sami Hashim	ORC
Jennifer Nasser	Obesity Research Center
Rich Bodnar	Queens
Anthony Sclafani	Brooklyn College
Gerry Smith	Weill Medical College
Douglas Mook	Queens
George Collier	Rutgers
Karen Acroff	Brooklyn College
Katherine Halmi	Cornell

Summary: (Outline provided by speaker, prepared in text by Rapporteur)

Dr. Lewis presented a seminar on alcohol, a substance which can be thought of in two ways: 1) as a drug of abuse with pharmacological effects, and 2) as a food that interacts with feeding neuropeptides. His talk focused on both of these dimensions.

As a drug of abuse, alcohol has a variety of effects. In the non-dependent drinker, alcohol acts as a sedative, hypnotic, stimulant, euphoriant, anxiolytic, analgesic, and an aperitif. Animal experiments also show that alcohol can have locomotor effects, can act has a reinforcer (positive or negative), and can affect motivation and food intake. Research in the area of alcohol dependence has been difficult because of the challenges of finding appropriate models of alcohol addiction in animals. Common research paradigms that are used in animals include self-administration of two-bottle choice tests, and testing the rewarding or positive reinforcing values inherent with alcohol. From these studies, it can be concluded that ethanol is a weak reinforcer.

Studies in the brain looking at how alcohol elicits it's reinforcing effects have been done by Dr. Lewis and, using a variety of methodology, including 2-deoxyglucose. Results of these studies suggest that alcohol increases dopamine release into the nucleus accumbens, so it's effects on the brain are similar to other drugs of abuse. Others research indicate the GABA-benzodiazepine systems are important in negative reinforcement. As a food, alcohol has a number of important links with nutrition. It contains 7 calories per gram, higher in energy density than proteins and carbohydrates, nearly as energy dense as fat. Alcohol consumption has been shown to increase concentrations of circulating lipids, indicating a possible role for alcohol in the exacerbation of certain disease states. Furthermore, food deprivation tends to increase consumption of alcohol, and alcohol consumption increases food intake.

In alcoholism, organ systems can begin to fail (liver, pancreas, and brain). Chronic alcoholics are usually underweight, as the metabolism and intake of carbohydrates is blocked, and the storage and metabolism of lipids is greatly reduced. Dr. Lewis and colleagues Drs. Bart Hoebel and Leibowitz and their labs have been investigating possible mechanisms for how alcohol dependence elicits these changes in feeding and metabolism. They studied a number of the neuropeptides that are potentially involved with this process, including galanin, orexin, and endogenous opioids (all of which increase intake).

Studies by this group found that there was a relationship between galanin, alcohol dependence, and feeding mechanisms. Leibowitz and colleagues found that chronic intake of a high-fat diet can stimulate the release of galanin and conversely chronic alcohol administration in animals increases the amount of galanin in the hypothalamus. Studies done with Bart Hoebel's lab in 2004 revealed that galanin microinjection into the third ventricle or the PVN increased voluntary alcohol intake. After 6 or more weeks of alchohol intake, galanin no longer did not increas food intake. Thus, galanin appears to play an important role in regulating the feeding alterations that take place during alcoholism. Recent research also shows that other neuropeptides (enkephalin, dynorphin) also are increased with alcohol administration. New genetic studies stimulated by this laboratory research show that some alcoholics have an association of galanin and one galanin receptor (GAL3) with alcoholism.

In summary, alcohol is both a drug and a food, and thus the mechanisms that reinforce abusive drinking in alcoholics are complex. It appears that the initial stages of abuse and during the development of dependence drinking is motivated by positive and negative reinforcing mechanisms similar to other drugs of abuse. Effects on dopamine and GABA-benzodiapine systems are clearly important in these effects. Later, with severe dependence and the deterioration of nutritional organ systems, alcohol's nutrient-related signals and effects on feeding mechanisms may become more important and sustaining in alcohol consumption.

Discussion:

Q. Why is it hard to get animal models of alcoholism?
A. Alcohol is aversive to most rodents. It is difficult to get randomly bred rats to drink it. Moderate consumption can be trained; however, it takes time and rats will not drink to intoxication.

Q.If you could describe the state that animals reached after alcohol self-administration, when you say "mild intoxication?"
A. There are some animals that drink to intoxication, but most do not. This is one of the problems with studying alcoholism using rat models.

Q. Is this orally consumed alcohol (when studying effects on locomotor behavior)?
A. No, it was IP injection.

Q. Why are cocaine and heroin commonly studied by microinjection into the brain, but we don't see a lot of studies doing that with alcohol?
A. Those studies have been done by Gatto and T-K Li colleagues at Indiana University, and you get some weak self-administration after microinjection into the brain.

Q. When is the inverse agonist (R015-4513) administered during the experimental paradigm?
A. Either before or after alcohol administration. In both cases, it will block effects of alcohol.

Q. Is this available for humans?
A. No, because it does not change the lethal effects of alcohol. It will only block the anxiolytic and locomotor effects of the drug.

Q. Is that true (the statement made by Dr. Lewis that food deprivation will increase alcohol intake) for both humans and animals?
A. It depends on the paradigm. Some have shown the effect, while others have not. It is reliable enough for there to be a class of alcoholic beverages called "aperitif".

Q. What do you think of the data that suggests a certain amount of alcohol can increase energy expenditure?
A. That is an important part of the literature, and I think that it can potentially have important implications.

Q. Is there a sex difference in handling alcohol in animals?
A. Yes, there are different effects of alcohol depending on the sex of the animal.

Q. From Sarah Leibowitz's work, galanin increases fat intake. Have you looked at that in your lab?
A. In early work in my lab, we did observe an increases fat intake with alcohol administration. However, that effect is complicated and we want to look at it again.

Q. Do the anxiolytic effects of alcohol predict the susceptibility to alcohol dependence?
A. That has been suggested, and yes, some our data suggest that as well.

Q. Is that related to the amount of alcohol dehydrogenase present?
A. That has not been shown to my knowledge..

Q. What about other forms of alcohol (such as bourbon, which is known to have over 100 compounds)?
A. There have been a few animal studies, but not much has come of it.

Q. Can you show in an alcohol dependent animal that the relapse is similar to other drugs? Will naltroxone stop relapse?
A. Yes, I think that has been shown. Naltrexone was actually the first drug approved for the treatment of alcoholism.

Q. Why does fat promote alcohol intake? This appears to be contradictory to the fact that alcohol is processed more similarly to carbohydrates.
A. I'm not sure. More people are currently interested in the interactions of alcohol with lipid production and metabolism.

Q. I always thought that it was the taste aspect that got people to drink. What is special about the nutritive effects of alcohol that stimulate it's intake?
A. I'm not sure, but I'd love to know. It's definitely different in the alcoholic than it is in the non-dependent drinker.

Q. If you take a dependent rat and dry them out, does that rat show a prolonged preference for alcohol?
A. It depends on what kind of rat it is, and how you make the animal dependent in the first place.

Q. Will an alcohol preferring rat sham feed alcohol?
A. I don't know. I do not think that it has been done. It would be a very good experiment.

Q. Have you seen any data looking at anxiety and depression tests in animals after taking alcohol away?
A. The animals don't typically drink enough on their own to see these effects. I do not think that anyone has published on the topic.

Q. Are there any explanations for why in epidemiological studies, there have been positive effects seen for 1-2 drinks / day?
A. As long as you do not exceed the liver capacity to metabolize the drug, you might see some health benefits. NIAAA states that there are cardiovascular benefits from such low daily consumption. The effect disappears if you exceed 1-2 drinks/day. The positive effects are seen with up to 2 drinks/day for men and 1 drink/day for women.