They say that absence makes the heart grow fonder. That may be true not just for loved ones, but for just about anything pleasurable. In fact, new findings from addiction research suggest that abstaining for a day or so from a pleasure such as alcohol, cigarettes or junk food could be the key to getting hooked on it.
The idea may seem counter-intuitive, even absurd. To stay off a drug, one has to stop taking it. The problem is that the effects of withdrawal from a drug during abstinence are apt to include, for the first few days at least, a greater desire for it, even a frank craving—so that the next intake will be higher, and so on until full-blown dependency sets in. “It’s a vicious spiral,” says Olivier George, an addiction researcher at The Scripps Research Institute.
For example, scientists have long known that when they give lab rats free daily access to alcohol, the animals do drink, but their intake soon plateaus—at a level that is too low to serve as a model for human alcoholism. To get the rats to escalate to alcoholic intake levels, researchers have to employ “assimilation procedures,” such as adding sugar to the alcohol, blocking the rats’ access to food and water, and even stimulating the pleasure centers of the rats’ brains, with implanted electrodes, while they drink. However, since the early 1970s it has been known that a schedule of intermittent drinking, with abstinence breaks of a day or so, leads rats to escalate their intake rapidly—and voluntarily, without assimilation procedures.
The intermittent access model wasn’t adopted in the 1970s, in part because the rats still didn’t escalate their intake enough to seem alcoholic. But several research groups have recently started working with this model again, as a way of studying human binge-drinking—a problem that wasn’t recognized as much in the 1970s. Perhaps even more importantly, these groups see the intermittent access model as a tool for studying how people move from occasional light drinking to full-blown alcoholism. It’s now clear that rats with access to drink only every other day or so typically escalate their intake far above that of daily-access rats, and also show some of the brain changes normally associated with alcohol dependency.
The abstinence-withdrawal-escalation effect appears to be relevant for nicotine intake, too. This past August, George and his colleagues reported on a study in which rats with extended access to nicotine for a day or two, then no access for a day or two, strongly increased their intake of the drug—whereas rats with daily extended access did not. These findings also are consistent with those from human studies of nicotine dependency. In young people, for example, even moderate, non-daily cigarette use frequently leads to escalation and dependent daily smoking. “It appears that withdrawal symptoms which include craving and irritability may drive early smoking escalation to daily use,” says Cheke Doubeni, a researcher at the University of Massachussetts Medical School, and lead author of a 2010 study of adolescent smokers.
The idea that even small exposures, followed by abstinence, can create a ratchet effect of increasing desire and intake, contradicts the traditional view of nicotine dependency. “The traditional view has been that addiction isn’t even possible until you’re smoking at least five cigarettes per day—that you’d have to get up to that threshold level of nicotine exposure first,” says Joseph DiFranza, a professor at the University of Massachussetts Medical School who has helped to pioneer research in this area. “Now we know from many studies that even after their first cigarette some people have a craving for nicotine. We also know that intermittent exposures of nicotine can have very long lasting effects on the brain—in animal studies, we still see effects on brain physiology a month after a single dose of nicotine.”
The stress factor
The escalation of drug intake with intermittent access appears to be mediated at least partly by the body’s stress circuitry. Stress is a known factor in full-blown dependency; alcoholics during withdrawal are likely to experience not only a craving for drink, but also negative, unpleasant sensations including anxiety and irritability. This is due largely to the release of the stress hormone CRF (corticotropin releasing factor) in a key section of the amygdala, a limbic structure that mediates emotional responses. The prefrontal cortex, which normally would suppress this limbic overactivity, is simultaneously weakened and more or less disconnected. Re-use of alcohol—what a drinker might call “steadying the nerves”—can temporarily alleviate these anxiety-related changes. In recent years, similar changes have been observed in rats whose intermittent access has led them to escalate their intake—and blocking CRF with drugs causes these high-intake rats to reduce their drinking. “We hypothesize that CRF mediates the high alcohol drinking seen in the intermittent access model because of the mini-withdrawals between periods of binge drinking, which can lead to stress,” says Lara S. Hwa, a researcher at Tufts University who has used this model.
In October, George and his colleagues reported finding what may be the earliest signs of this CRF-related, dependency-driving process, in rats with intermittent but still modest alcohol intake. In these animals, a distinct population of neurons (including CRF-releasing neurons) in the medial prefrontal cortex became strikingly overactive—compared to the same neurons in everyday-drinker rats—on abstinence days. The net effect was to suppress the primary prefrontal circuitry that normally helps an animal maintain executive control over its behavior. This change occurred even before any evident sign of anxiety in the animals. “The suggestion of this study is that such brain changes might arise very early, when you are drinking in a binge-like pattern, and will enable the transition from recreational to binge-drinking to heavy drinking,” George says.
Strikingly, the abnormal neuronal activation seen in the intermittent-drinker rats on abstinence days disappeared as soon as they were allowed to spend two hours drinking. And the abnormal activation didn’t appear at all in the daily-drinker rats. “They didn’t show any sign of brain dysregulation, and their intake of alcohol was very stable, even after months of drinking,” says George. “They just drank a bit like the French way, a couple glasses of wine every day.”
George and his colleagues are now setting up further studies to better understand these early brain changes and their relationship to CRF and stress, and also to look at the apparent mutual-escalation interaction between smoking and drinking.
Meanwhile, other researchers have been finding a similar abstinence-and-escalation effect for food intake. Eric Zorrilla, also at Scripps Research, studies a variety of rat models of intermittent access to rich, sugary, fatty (“highly palatable”) food. “All of the intermittent access models produce pretty dramatic overeating upon renewed access,” he says. “The speed at which the rodents overeat the palatable food upon renewed access is directly related to how limited their access to it has been in the past.” Once the rats have escalated their intake to binge levels, their withdrawal signs on abstinence days are accompanied by upregulation of CRF in the amygdala. “If we administer a CRF1 antagonist to these intermittent-access ‘escalated’ rats, it normalizes their intake, getting them to eat more of their blander chow diet while reducing intake of the highly palatable diet,” Zorrilla says.
Drugs that target the CRF system are already being investigated as treatments for addiction. Results such as George’s and Zorrilla’s hint that they might work as preventives of addiction as well. Another, potentially controversial implication of this research is that the daily use of something pleasurable may be safer than intermittent use, if only because it is more likely to keep cravings at bay, and thereby keep intake from escalating beyond a modest level.
“It’s like the title of that country music tune, ‘How Can I Miss You When You Won’t Go Away?’” says DiFranza.