Like many people, rats are happy to gorge themselves on tasty, high-fat treats. Bacon, sausage, chocolate and even cheesecake quickly became favorites of laboratory rats that recently were given access to these human indulgences—so much so that the animals came to depend on high quantities to feel good, like drug users who need to up their intake to get high.



A new study, published online March 28 in Nature Neuroscience, describes these rats' indulgent tribulations, adding to research literature on the how excess food intake can trigger changes in the brain, alterations that seem to create a neurochemical dependency in the eater—or user. (Scientific American is part of Nature Publishing Group.) Preliminary findings from the work were presented at the Society for Neuroscience meeting in October 2009.



Like many pleasurable behaviors—including sex and drug use—eating can trigger the release of dopamine, a feel-good neurotransmitter in the brain. This internal chemical reward, in turn, increases the likelihood that the associated action will eventually become habitual through positive reinforcement conditioning. If activated by overeating, these neurochemical patterns can make the behavior tough to shake—a result seen in many human cases, notes Paul Kenny, an associate professor in the Department of Molecular Therapeutics at The Scripps Research Institute in Jupiter, Fla., and co-author of the new study. "Most people who are overweight would say, 'I would like to control my weight and my eating,' but they find it very hard to control their feeding behavior," he says.



Despite a growing body of research, it has been unclear whether extreme overeating was initiated by a chemical irregularity in the brain or if the behavior itself was changing the brain's biochemical makeup. The new research by Kenny and his colleague Paul Johnson, a graduate student, shows that both conditions are possible.



Bigger waists, higher thresholds

To see just how overeating and obesity alters the brain's reward circuitry, the researchers implanted stimulating electrodes in rats' brains to monitor their changing reward threshold levels. Some rats were given only one hour a day to feast on tasty, high-fat foodstuffs, whereas others had almost unlimited access (18 to 23 hours a day). All the rats, including a control group that was given no human food, had open access to water and standard, healthful lab rat chow.



Unsurprisingly, the rats with extended access to the high-fat foods ate little to none of their comparatively bland lab fare and quickly grew obese—consuming about twice the amount of calories as the control, chow-only group. The researchers also found that even the rats with limited access to the unhealthful food were doing their best to keep up. These subjects managed, on average, to consume 66 percent of their daily calories over the course of the single hour per day in which they could eat the junk food, developing a pattern of compulsive binge eating. Only the obese rats with extended access to the bad food, however, had sharply increasing thresholds for reward levels.



"This research by Kenny's group is a great contribution," says Nicole Avena, a visiting research associate at Princeton University's Department of Psychology who was not involved in the new study but has completed similar research on addiction and high-sugar diets. Many studies have drawn the connection between excessive food intake and addiction in both animal models and humans. A 2001 study in The Lancet observed a similar dearth of dopamine receptors in the brains of many obese people as in those hooked on cocaine or alcohol. The new research adds a more nuanced understanding of just how food can modify the brain—and shows that differences in the brain from the outset can predispose an individual for overeating.



Engineering an overeater

To start an addictive cycle, dopamine must be felt, and for that the brain must have ample dopamine receptors. In many substance abusers a low level of dopamine receptors, either from the outset or caused by the behavior, means they increasingly have to seek more dopamine-inducing substances to reach a level of neurochemical reward they can enjoy. After someone dependent on a substance stops using it, however, it often takes time for depleted dopamine receptors to return to baseline levels. For mice addicted to cocaine, it can take two days to regain normalized levels. The obese rats in the new study took two weeks to regain their baseline density of receptors.



To gauge just how much the quantity of dopamine receptors had affected the rats' eating behavior, Kenny and Johnson inserted a virus into the brains of a test group of the animals to knock out their striatal dopamine D2 receptors, which are known in humans to be at low levels in many substance abusers. They found that rather than gradually increasing rat brain reward thresholds and accompanying overeating behavior these rats almost immediately had higher thresholds and took to overeating immediately when given access to a high-fat diet. This connection, Kenny says, shows that for people who have lower levels of D2 receptors, "it could predispose you to developing this kind of habitual behavior."



Genetics likely play a role in an individual's likelihood of becoming obese—in both metabolic and neurochemical systems. In humans, for example, one genetic flag known as the TaqIA A1 allele has been linked to fewer D2 receptors as well as drug addiction and obesity. And in the rats there were "occasionally one or two animals per study that didn't overeat," Kenny says. He and his colleagues are currently investigating possible genetic underpinnings of this phenomenon to see if there is a similar genetic marker that could be useful in helping humans avoid obesity. Further findings in this field might help in developing new prevention and treatment possibilities. Counseling techniques, therapy and even pharmaceutical treatments that have shown success for substance abuse might show promise for those who struggle with overeating, Kenny notes.



Looking outside of the current repertoire of treatments might be important, as dieting alone has often proved to be an unsuccessful long-term strategy for people who struggle with overeating. The new study showed that after eating a diet full of sausage and sweets for 40 days—even though regular lab rat chow was available—the obese rats had little interest in reverting to the more healthful diet when the tasty stuff was taken away. In fact, after depriving the high-fat habituated rats of their human junk foods, the rats would refuse to eat their standard chow for an average of 14 days. "I was really shocked at the magnitude of the effect," Kenny says. "They basically don't eat anything. If that translates over to us as a species, that's a major problem."



Fighting foods

The sticky part about studying food addiction is that, unlike cocaine or alcohol, humans can't exactly drop it—cold turkey or not. "You can't really quit food," Avena says. And humans are hardwired, thanks to eons of evolutionary selection, to seek high-calorie foods to keep us going through lean times. But with subsistence hunting, gathering and farming now little more than a niche lifestyle choice in wealthy nations, a brain set up to reward super-rich calorie snacks is more of a hazard than a help.



"In one sense, we're all addicted to food," Kenny says. He points out, however, that many of the food items widely available today, say cheeseburgers and milk shakes, are like superfoods in terms of their calorie quantities. "This energy-dense stuff is very new to us as a species. It's probably corrupting brain circuitry," he says.



Unlike rats, however, most people know that many of these high-fat foods are not a wise choice, especially when consumed in large quantities. But many continue to eat in excess of basic energy requirements anyway, putting on unnecessary pounds and possibly reinforcing unhealthful behavior. So the researchers designed an experiment to try to draw a parallel with the rats, training them to expect an electric shock when they saw a certain light cue. Unlike their chow-fed counterparts, obese rats accustomed to the high-fat diet would keep right on gorging even when they knew a shock was coming.



Although the current work focused on high-fat foods, Kenny notes that the full neurochemical and behavioral changes might be due to "a combination of both sugar and fat." Avena and her colleagues have been working to parse out the various nutrients in potentially addictive food products and what impact they have on the brain. They found, for example, that animals binge-eating fats and animals binge-eating sugars experience different physiological effects. "They affect the brain in very different ways," Avena says.



The big one-two punch for defeating healthy eating might in fact be a combination of neural effects from both of these ingredients. And, indeed, the sweet spot for the lab rats in Kenny's study seemed to be the food item that contained high quantities of both fat and sugar: cheesecake. Sara Lee, to be precise, Kenny reports.