Date: September 17th, 2009

Speaker's Name and Affiliation:

• Nicole Avena
• Rockefeller University

Seminar Title: "Addictive-like properties of sugar and fat bingeing in rodents"

Chair: Harry R. Kissileff, Ph.D.

Rapporteur: Kathleen L. Keller, Ph.D.

Attendees and their Affiliation:

Kathleen Keller	Columbia/Obesity Research Center
Harry Kissileff	Obesity Research Center
Tony Sclafani	Brooklyn College
Michael Lewis	CUNY Hunter College
Timothy Walsh	Columbia Psychiatry
Jennifer Nasser	St. Luke's
Debra Zellner	Montclair State
Karen Ackroff	Brooklyn College
Charlesa Gibson	St. Luke's/ NYORC
Susan Carnell	St. Luke's ORC
Carol Maggio	ORC
Joseph Vasselli	ORC
Rich Bodnar	Queen's College
Allan Geliebter	NYORC
Miranda Johnson	UMDNJ
Barry Levin	VA Medical Center
Keesandra Agenor	Barnard College/ St. Luke's NYORC
Camille Boussant	St. Luke's / NYORC
Yasmine Lahssini	St. Luke's / NYORC
Davelene Israel	Albert Einstein
John G. Kral	SUNY Downstate

Summary: (Prepared by the Rapporteur)

Obesity is a serious public health problem in the United States. A variety of reasons may explain why people are overweight, but in Dr. Avena's talk, she focused on the idea that high-fat, high-sugar foods are ubiquitous and tasty, and because of this, are often consumed to excess. The question was raised as to whether some people develop "addictive-like" symptoms when placed in an environment where high-fat and high-sugar foods are abundant.

It is well known that drugs of abuse can exert "addictive-like" behaviors in both laboratory animals and humans. These include escalation of intake (sometimes in the form of binges), withdrawal signs in the case of opiates, and craving when the substance of abuse is no longer available. The neural circuitry common to both food and drug addiction involves dopamine neurons that originate in the ventral tegmental area and project to the nucleus accumbens and prefrontal cortex. Both drugs of abuse and food increase extracellular dopamine in these brain areas upon administration, and repeated administration results in sensitization to these signals. A difference between the effects of drugs and food on the dopamine system is that dopamine release normally habituates in response to a palatable food that is no longer novel, while the release of dopamine occurs each time a drug of abuse is administered. In addition, acetylcholine release increases during drug withdrawal, or during states of satiety at the end of a meal.

In order to study the addictive-like properties of food, Dr. Avena and colleagues have developed an animal model of sugar bingeing. Sprague-Dawley rats are fasted for 12 h followed by 12 h of access to a 10% sugar solution, starting 4 h into the dark phase, for 1 month. This paradigm results in animals that binge on sugar and increase daily intake of sugar throughout the test period. In vivo microdialysis to measure extracellular dopamine and acetylcholine in these animals shows that dopamine release in the nucleus accumbens repeatedly increases in sugar-bingeing rats, but not in controls. This suggest that sugar bingeing can result in the repeated release of dopamine in the nucleus accumbens, which is more like the effect seen in response to drugs of abuse and unlike the waning of dopamine release that would normally be seen in response to food. In addition, acetylcholine rises at the end of a sugar meal for both controls and bingeing animals, but this rise is delayed on day 21 in the sugar-bingeing rat.

The next question addressed in this seminar was whether the taste of sugar drives this alteration in dopamine and acetylcholine release. To test this, an animal model of bulimia nervosa was developed, which combined sugar bingeing and sham feeding. The results demonstrated that sham-fed rats have larger binges on sugar compared to the real-fed animals. Further, sham-feeding while bingeing on sucrose resulted in increases nucleus accumbens dopamine release, but acetylcholine failed to rise at the end of the meal in sham-fed, sugar-bingeing rats. This suggests that the taste of sugar is sufficient release accumbens dopamine and attenuate the release of acetylcholine, and perhaps satiety, in sugar-bingeing rats.

In addition, other signs of addiction are noted in sugar-bingeing rats. These rats show behavioral and neurochemical signs of withdrawal (precipitated with naloxone or spontaneously) similar to those seen with drugs of abuse. After a 2-week abstinence period, sugar-bingeing animals show enhanced intake of sugar, which suggests that these animals "crave" the sugar. Further, sugar-bingeing rats show a hyperactive response to a low dose of amphetamine and more readily consume alcohol compared to animals that are not sugar-bingers, suggesting that cross-sensitization to drugs of abuse is evident.

A final important question addressed by this seminar was whether this model of sugar bingeing can explain the development of some forms of human obesity. In rats, sugar-bingeing does not result in increased body weights, as these animals reduce intake of chow to compensate for the extra calories obtained from the sugar. Other sugars, such as high-fructose corn syrup, may differentially effect body weight regulation. In a model of fat bingeing using a paradigm that is similar to that used to produce sugar bingeing, opiate-like withdrawal signs were not observed. Thus, the differences that exist between sugar and fat bingeing, and the "addictive-like" nature of each, have to be further investigated.

Discussion:

Q. Do you think that anything that is rewarding can also be addicting?
A. Based on the described neural circuitry, I think that anything that has the potential to be rewarding can be addicting.
Comment: From the criteria that you have listed on addiction, it seems that anything that can be rewarding (e. g. video games, shopping, gambling) can also be addicting.
A. Yes, that seems so.

Q. Anna Rose Childress has an interesting model on relapse susceptibility that is related to the ability to activate GABA systems. Susceptibility to relapse relates to how efficient you are to activation of the GABA system.
A. Yes, I have heard of that.

Q. Could intoxication be a distinguishing factor in your model, with respect to "food addiction?" People don't become intoxicated by food.
A. That's true.
Comment: Tolerance and withdrawal are separable concepts, but Koob linked them. The initial phase of taking drugs is different from states that occur down the line. During dependence, you no longer report that the drug is rewarding. This entire cycle is "addiction."
A. I think this illustrates the point that I am trying to make, that addiction is not easily quantified.

Q. In Kent Berridge's work where you mix and match drugs and food, he shows that with repeated administration you get sensitization. This is very different from the classical addiction model. This repeated injection paradigm never results in tolerance. Maybe the terminology should be changed?
Comment: The point is that some drugs do not fit the definition of heroin addiction. There are some in the field that believe that heroin/opiate addiction is the only drug that fits this definition of addiction.

Q. What is the evidence that humans binge on sugars?
A. Most probably don't binge on pure sugar, but we did our experiments with just sugar so we could isolate the effect of one nutrient at a time.

Q. What supplier did you use for your Sprague-Dawley's? Some of the Sprague-Dawley's are less resistant to obesity than others.
A. We use Taconic.

Q. The data that you are showing now is with sucrose, right?
A. No, it's glucose.

Q. The ad libitum rat is fed, but the bingeing rat is not, correct?
A. Both rats are fed, but the difference is that the ad libitum rat has 24 h/day access, while the bingeing rat has access for only 12 h/day. I think the data that I will present looking at meal patterns will clarify that question.

Q. Is this total food or glucose?
A. This is just glucose. The bingers appear to decrease their chow intake to compensate for the extra calories obtained from the sugar.

Q. What is time zero?
A. 4 hours

Q. Do you see a wide variability in sucrose preference?
A. We haven't measured that formally.

Q. Do your dopamine levels differ in response to sucrose vs. glucose?
A. We see about the same dopamine response. Only the animals that are bingeing on sucrose and have everyday access continue to release dopamine.

Q. Does this effect occur in relation to amount of sucrose, or is it in response to just the taste of it?
A. Andras Hajnal has published on this, and he will probably speak to that at the next seminar.

Q. When are you doing the dialysis for measuring dopamine?
A. While they are drinking.

Q. How can you control for that?
A. Hajnal has done that. He's speaking next month.

Q. Do you see a correlation with the concentration of sucrose used?
A. We've only used 10%.

Q. On day 1, when neophobia might be a factor, do all rats go for the sugar?
A. Most rats will drink some, but there is a learning curve and they consume more over time (i.e., over the course of the experiment to day 21).

Q. When was the test done with naloxone in relation to their food intake?
A. Naloxone was administered at the time when they would normally binge, which 4 h after the onset of the dark.

Q. What happens if on day 22, you don't give them sugar? Do they go through a behavioral withdrawal?
A. Yes, we can see it happen spontaneously when they are fasted for 24-36 h.

Q. Do you know whether anxious humans or animals binge on sugar?
A. I can't point to any studies that have looked at that.

Q. Can you induce spontaneous withdrawal if you use a dopamine antagonist and then give sugar?
A. We haven't done that yet.

Q. Is there any data showing that High Fructose Corn Syrup causes dopamine release?
A. We haven't done that yet, but I would suspect that it does.

Q. Did you try using fat emulsions?
A. Yes. These did not induce withdrawal either.

Q. Did you try Ensure?
A. Yes. This didn't work either.

Q. Isn't there a time induced effect? If you are looking at gene expression (mRNA), this would take 24 hours, but behavioral withdrawal symptoms (e.g., teeth chattering) appear almost immediately.
A. That's true.

Q. Food deprivation increases the administration of all drugs of abuse. Have you tried this condition yet?
A. We have.

Q. How does acetylcholine affect fat bingeing?
A. We haven't tested that yet.

Q. Your fat bingeing test paradigm is different from your sucrose paradigm, right?
A. Yes, that's true. We used a different schedule in that study.