Kappa delta mu sounds like a college fraternity. And if you associate college with sometimes fatal outbursts of binge drinking, the Greek letters might be a fitting label.
For neuroscientists, though, kappa, delta and mu refer to opioid receptors, large molecules found on the surface of neurons. Opioids, literally "resembling opium" — which stems from the Greek word opion, or "poppy juice" — are a group of natural substances produced by the opium poppy plant. Similar-acting substances are also produced by the body when we are stressed or when we are anticipating reward. Think endorphins.
Neuroscientist Howard Fields, MD, PhD - a senior researcher at the UCSF-affiliated Ernest Gallo Clinic and Research Center and director of UCSF's Wheeler Center for the Neurobiology of Addiction — believes that small differences in receptor activity might be a major culprit in alcoholism. And in part 1 of "Alcoholism: Vice or Disease," he argued that addicts are more victims of biochemistry than of bad judgment.
"I want to be clear, though," Fields adds. "Higher degrees of impulsivity [the genetics of which are still being worked out] seem to be a risk factor for alcoholism. But if you grow up in a Mormon community where there is strong pressure against drinking alcohol, you probably will not become an alcoholic. Take that same person, though, and put him or her in an environment where there is a lot of stress and people are relieving their anxiety by drinking, and the results might be very different. We have to always remember that there are a lot of reasons why people drink."
And a lot of theories. Fields acknowledges that the opioid receptor hypothesis is only one of many, and none are yet proven. In addition to opioids, some scientists favor the GABA receptor theory; GABA, short for gamma-amino butyric acid, is a neurotransmitter, a substance that governs how electrical signals pass between cells.
Serpentine mu opioid receptor. Image courtesy of Van Warren, Receptor World
"There are some scientists," says Fields, "who think alcohol is addicting primarily through a direct action on GABA receptors that indirectly activates dopamine neurons. It's true that alcohol does produce an increase in dopamine concentration in the brain, where we know that feelings of reward originate. And we know that rats bred to like alcohol will choose a lever to deliver alcohol directly into the region of their brains where there are dopamine neurons."
Yet there is another principle at work that Fields finds equally fascinating. It involves satiety, or — more accurately — the failure of satiety to literally signal "enough is enough."
"When we eat, we eventually get full, and eating is no longer pleasant. That's the satiety mechanism at work. What if alcoholism is a failure of satiety? What if alcoholics keep drinking because they never feel like they've had enough? Maybe alcohol is handled a lot like food."
Animal models reveal that endorphins acting at the mu subtype of opioid receptor promote eating and suppress satiety. Conversely, endorphins activating the kappa receptor promote satiety. So what about the endorphins released in the brain when someone drinks alcohol? Where do they go?
That's what Fields and his colleagues are trying to nail down. Questions abound. "Are there equal numbers of receptors?" he asks. "Do different endogenous opioids act on mu and kappa receptors? Is the balance between a mu receptor that promotes drinking and a kappa receptor that suppresses drinking at least partially responsible for how much you drink?"
The answers might finally pinpoint where exactly alcohol acts to produce its powerful sense of reward. That region — or the molecular activity within it — then becomes a potential drug target. In Fields' mind, it boils down to this: "What we're doing in my lab is using animals to find out what would be the ideal combination of receptor agonists and antagonists to maximally reduce drinking, then try to design a molecule that would have those properties."
For now, naltrexone remains one of the few drugs effective for treating alcohol addiction. The operative word here is "treat," not cure. Still, if you ask law enforcement and probation officials in Butte County, California, what they think about naltrexone treatment for alcohol abusers, particularly repeat offenders tempted to get behind the wheel again, the answer would likely be applause. Indeed, the latest figures show a 30 percent drop in recidivism among those required to take the drug.
"Naltrexone is effective," says Fields. "It reduces the amount you will drink, which means that for many people, it's the difference between two drinks and five drinks. But getting people to stay on it is tough. And it might not work for everyone, maybe because it blocks both the delta and kappa receptors. Activated kappa receptors suppress alcohol intake. So if you block them, like what some have done in animal studies, you could be creating conditions where some people drink more while taking naltrexone instead of less."
Another drug, called rimonabant (Acomplia), now being sold in various European countries as an anti-obesity drug, also seems to reduce both cigarette smoking and alcohol intake, although its increased risk of depression has made the US Food and Drug Administration wary. Nonetheless, if approved, rimonabant's off-label use could rival its primary purpose.
Fields wouldn't mind the competition. "Based on the research going on here and other places in the US and around the world, I would say that in the next five to 10 years, addiction treatment is going to be markedly improved by the introduction of new pharmacological agents."
But will it matter? In part 3 of "Alcoholism: Vice or Disease?" we will discuss why some in the treatment community still seem to favor the bootstrap over the pill bottle.
- Receptor World
- A Message from the Director
- Wheeler Center for the Neurobiology of Addiction
- Howard Fields
- Wheeler Center for the Neurobiology of Addiction
- Howard Fields
- Ernest Gallo Clinic & Research Center
- A is for Addiction Research
- UCSF Magazine, August 2002
- Alcohol History in America
- History of Alcohol
- History of Alcohol and Drinking Around the World
- Sociology Department, State University of New York, Potsdam
- The Social History of Alcohol and Drugs: An Interdisciplinary Journal
- Alcohol and Drugs History Society
- National Institute on Drug Abuse, NIH
- FAQs for the General Public
- National Institute on Alcohol Abuse and Alcoholism, NIH
- Prevention Online
- National Clearinghouse for Alcohol & Drug Information, U.S. Department of Health and Human Services