Can food be addicting? Anecdotal evidence and the rising tide of obesity would suggest so, but tales of compulsive eating disorders do not substitute for the reality of scientific data. Enter Larry Tecott, a UCSF professor of psychiatry and an investigator at the Wheeler Center for the Neurobiology of Addiction. "There certainly is something driving people to eat more than they need and certainly there is a lot of pleasure associated with eating. It stands to reason that there might be links in the brain between overeating to the point of obesity and abusing drugs to the point of addiction."

Indeed, Tecott, who will be among the first wave of researchers moving to UCSF's Mission Bay campus, is pinpointing at least one definite link between such "disordered ingestive behaviors": namely, a single receptor protein that sits on the surface of certain brain cells amid a so-called reward pathway. This pathway consists of cellular circuits that influence just how strongly an individual will respond to a pleasurable experience, whether it is a piece of pie or a snort of cocaine. Tecott has found that mice, genetically altered so that they are missing just that one receptor, eat 20 percent more than normal mice. And he expects that experiments now in progress will show those transgenic mice have a much stronger drive to consume cocaine, too.

Tecott did not set out to discover a link between overeating and drug abuse. Like many psychiatric researchers, he sought to better understand how the neurotransmitter serotonin worked. "I'm not aware of any complex behaviors that cannot be influenced by some type of manipulation of the serotonin system." To be sure, serotonin is the target of many psychiatric medications, perhaps most famously Prozac, which increases serotonin's availability to combat depression. But such drugs often produce side effects because there are at least 14 sub-types of receptors - sites where serotonin binds to a cell to pass along its chemical message - and each responds differently: Some may affect mood positively, others may suppress sex drive or cause sleepiness. Better drug therapies should emerge from understanding each receptor's specific effects.

In the mid-90s, Tecott and his colleague, Wheeler Center investigator David Julius, created genetically altered mice missing a single serotonin receptor called 2C. These mice, Tecott noticed, overate. Over time, as their metabolisms appeared to burn fewer calories, they became moderately obese — a mouse version of the "middle-age spread." Moreover, as Tecott suggests, the serotonin 2C receptor is significant not only because eating behavior is partially voluntary, but also because it may alter appetites for pleasurable experiences, whether they be eating or taking drugs of abuse.

Here's roughly how it works. Cells called neurons extend between different brain regions and affect one another by their release of neurotransmitters. One way that feelings of pleasure are generated is by the release of the neurotransmitter dopamine in the limbic system, a set of brain structures involved in the regulation of emotion. Some dopamine-generating neurons extend to the limbic system from a mid-brain region known as the ventral tegmental area or VTA.

Meanwhile, serotonin routinely released in the VTA activates 2C receptors on cells called inter-neurons. As a result, those cells release a transmitter called GABA which, in turn, reduces the dopamine released to the limbic system.

"If you have less dopamine, you might get less pleasure out of your food. Your drive to want to consume it, your pleasure pathway, may be turned down," Tecott explains.

Hypothetically then, the mice without 2C receptors lack that serotonin "brake" on their dopamine pleasure pathway. Food and drugs of abuse that increase dopamine — such as cocaine - will produce a "bigger pleasurable boost," increasing the appetite for them, Tecott says.

Further reinforcing this point, experiments by Tecott's lab have employed a powerful appetite suppressant drug that works by increasing serotonin levels (D-fenfluramine, part of the Fen from Fen-phen, a diet drug combo pulled from the market in the 1990s due to dangerous cardiac side effects). The drug had little effect on the eating habits of mice missing their 2C receptors. The result: Several drug companies are now trying to create molecules that selectively stimulate the 2C receptor in order to reduce appetite without side effects.

The complete deletion of the 2C receptor in Tecott's transgenic mice undoubtedly produces much more clear-cut and dramatic effects than the very subtle variants of the same receptor that are found in humans. And he stresses that this reward circuit is only one way in which this receptor mutation may influence overeating; and that circuit is, in turn, just one of numerous ways in which the brains of mice and humans manage their appetites and pleasures.

But by demonstrating a single receptor's strong influence on a compulsive and ultimately health-damaging behavior (in another study, the overeating 2C-deleted mice were more prone to diabetes), Tecott's lab has drawn a rich parallel to drug abuse, one that suggests new modes of treatment.

"In addition to suppressing feeding, there's a lot of evidence now that stimulation of serotonin (or perhaps drugs that more specifically activate the 2C receptor) will suppress taking drugs of abuse," Tecott notes.

And while actual food addiction remains a controversial concept, as every dieter knows, trying to regain a healthy weight after habitual over-indulgence typically results in craving and relapses. "I think when you achieve a certain level of obesity, it produces long-term changes in the brain," says Tecott. "How these changes relate to the long-term changes associated with drug addictions is an important problem for further study."

Source: David Jacobson

Last updated January 28, 2005

Larry Tecott

Larry Tecott, a UCSF invesigator in the Wheeler Center for the Neurobiology of Addiction, is exploring the correspondence between abusing drugs and overeating to the point of obesity. Photo by Robert Foothorap.