Addiction at a Distance:
Brain Reward Decreases and Danger of Relapse Increases with
Heavy Cocaine Use
By Jason Socrates
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 elevatedperhaps
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 bloodbrain
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 usera
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 highthat
doing the drug was so enjoyablewhich 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 samethe drug continues to be
absorbed, cleared from the blood, and metabolized in the same
way. And the euphoria associated with the cocaine remains
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
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
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
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