Addiction at a Distance:
Brain Reward Decreases and Danger of Relapse Increases with Heavy Cocaine Use

By Jason Socrates Bardi

A group of researchers from The Scripps Research Institute (TSRI) have experimentally demonstrated the validity of a new hypothesis of drug addiction that may have important implications for treating chronic cocaine addicts.

The hypothesis holds that the body responds to the prolonged and escalated use of cocaine that accompanies cocaine addiction by establishing a new "hedonic set point"—the point at which euphoria is achieved. Over time, this set point is elevated so that it takes more of the drug to achieve the same effect, which in turn elevates the hedonic set point further.

After cocaine use is stopped, the set point remains elevated—perhaps for months after the drug has worn off. The TSRI group demonstrated that this "allostasis" of the hedonic set point correlates with increased relapse into cocaine use during withdrawal. Allostasis is a concept in physiology where an organism maintains the stability of a physiological parameter outside of the homeostatic (normal) range.

"This is the first demonstration that the depression and anhedonic effect one sees in withdrawal of drugs of abuse, particularly cocaine, is very long lasting," says Athina Markou, who led the study, which will be published in an upcoming issue of the journal Nature Neuroscience.

Cocaine's Costs to Society

Americans spend more on cocaine than on all other illegal drugs combined, says a White House Office of National Drug Control Policy study that came out in the mid-1990s. The study estimates that $38 billion was spent on cocaine in the years 1988 to 1995 alone.

These costs are a small wedge of the total pie. Cocaine's secondary costs to society due to cocaine treatment and prevention programs, emergency room visits and other healthcare costs, lost job productivity, lost earnings, and costs to society through cocaine-related crime, incarcerations, investigations, and social welfare are estimated to be in the billions of dollars annually. And the drug's human toll is of even more alarming proportions. Cocaine abuse is a major public health problem in the United States today. According to the National Institute on Drug Abuse (NIDA), there are nearly 2 million regular cocaine users, and cocaine is the leading cause of heart attacks and strokes for people under 35.

Cocaine, a chemical extracted from the leaf of the Erythroxylaceae coca plant, is a highly potent salt when it is consumed in soluble powder form that users snort or dissolve in water and inject. The salt is frequently neutralized to make an insoluble "free-base" form that is smoked.

Once in the bloodstream, the drug crosses the blood–brain barrier and accumulates rapidly in the ventral tegmental area of the brain.

This area is connected by nerve cells to the nucleus accumbens, the so-called pleasure center of the brain. There, the cocaine molecules interfere with the normal regulation of dopamine by binding to dopamine transporters and blocking them from recycling the neurotransmitter.

This leads to the build-up of dopamine in the brain's pleasure center, which produces a euphoric feeling in the user—a quick rush that hits seconds after the user takes the drug and lasts several minutes.

The New Hypothesis

Relapse, unfortunately, is a reality for many addicts. Addicts continue to crave the drug and are vulnerable to relapse into drug use for extended periods of time after stopping use of cocaine. For many years, scientists believed that the basis of relapse was positive reinforcement of the high—that doing the drug was so enjoyable—which conditioned the addicts to return to the drug.

But in recent years, a new theory has arisen that claims risk of relapse in cocaine addiction is a legacy of the neurological effects of prolonged cocaine use. The positive reward of taking cocaine remains the same regardless of whether one is chronically addicted to cocaine or not. It is the negative effects associated with the neurological changes that take place while a heavy cocaine user is on the drug that drive addiction.

The new theory arose, in part, because scientists like TSRI's Markou have developed the ability to monitor cocaine use and the activity of the brain reward system in laboratory models.

In this and earlier studies, Markou and her colleagues found evidence that the brain's reward system changes during prolonged cocaine use, particularly with regard to the hedonic set point, and that this hedonic allostasis is long lasting and is correlated with vulnerability towards relapse.

During hedonic allostasis, the absolute magnitude of the effect of cocaine is the same—the drug continues to be absorbed, cleared from the blood, and metabolized in the same way. And the euphoria associated with the cocaine remains the same.

What changes is the amount of cocaine one must ingest to achieve that euphoria. And the amount keeps getting larger.

"The drug has the same effect, but the hedonic set point is at a different level," says Markou.

Once a new hedonic set point has been established, it takes more cocaine to reach this point. The increase in cocaine consumption then pushes the hedonic set point even further.

This only happens when there is extended access to large amounts of cocaine, which allows for an escalation in cocaine use over time. Under such conditions, the hedonic set point increases, and the amount of drug that must be taken to achieve euphoria also increases. This leads to further drug intake and further alteration of brain reward neurobiology.

The results of this latest study suggest that in chronic cocaine use, tolerance and risk of relapse are related to hedonic allostasis.

It is this negative reinforcement, rather than the positive one that drives addiction to cocaine. The addicts may not be seeking pleasure as much as they are seeking to quell their bodies' inability to deal with a cocaine-altered brain reward system.

The current study is also one of the first demonstrations that this risk of relapse is long-lasting.

"Normal brain reward function is a limited resource," says TSRI Professor George Koob, "High amounts of cocaine deplete that resource and lead to an allostatic state."

"Translated into the human condition," he adds, "large amounts of cocaine leads to diminished reward in normal pleasurable activities, and that leads to more cocaine use and [the continuation] of the subsequent vicious cycle."

The investigators are now attempting to identify possible treatments based on these findings that might prevent addicts from relapsing into drug use.

The research article "Neurobiological evidence for hedonic allostasis associated with cocaine use" is authored by Serge H. Ahmed, Paul J. Kenny, George F. Koob, and Athina Markou and was published online on June 10, 2002 in advance of its publication in an upcoming issue of the journal Nature Neuroscience.

The research was supported by the Centre National de la Recherche Scientifique (France), the Peter McManus Charitable Trust, and grants from the National Institute on Drug Abuse (United States).


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Cocaine is a chemical extracted from the leaf of the Erythroxylaceae coca plant. The example shown here was cultivated at the Kiel University Institute of Pharmacy in Germany. Image by Thomas Schoepke --











In this and earlier studies, Markou and her colleagues found evidence that the brain's reward system changes during prolonged cocaine use...














"Normal brain reward function is a limited resource,"

—George Koob