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Addiction And The Problem Of Relapse

Addiction and the problem of relapse (Harvard Mental Health Letter, January 2007).

Research on the brain is showing that addiction is a matter of memories, and recovery is a slow and hesitant process in which the influence of those memories is diminished.

Studies have shown that the initial target of addictive drugs is a circuit in the middle of the brain centering on a region called the nucleus accumbens. It is sometimes called a reward circuit because if it is functioning properly, it provides pleasure or satisfaction when we experience something that is directly or indirectly useful for survival or reproduction.

The reward circuit provides incentives for action by registering important events and experiences and their adaptive value. Rewarding experiences cause the release of the neurotransmitter dopamine, telling the brain: “Do it again.” The brain records what “it” is through connections to centers of memory and emotion in the amygdala and hippocampus. Control centers in the frontal cortex use this information to judge the value of the reward, compare it with other rewards, and make plans. Dopamine activity increases not only when the brain is obtaining a reward but when it anticipates one.

Addictive drugs subvert the system by issuing a particularly powerful jolt to the nucleus accumbens. When used habitually, they deplete the supply of dopamine and interfere with the feedback between different parts of the brain that coordinate desires with priorities and expectations. Eventually, desire for the drug may trump most other desires. The drug no longer provides much pleasure, if any, but everything else is providing even less. Meanwhile, the brain is still receiving difficult-to-resist signals of imminent reward that command the addict to take the drug again.

These changes by themselves do not make addiction inevitable. Quitting temporarily can be easy. People addicted to alcohol, opiates, or cocaine can go for months, even years, without the drug. What makes permanent recovery difficult is drug-induced change that creates lasting memories.

Addicts have learned too well to expect a rewarding experience from the drug. After a while, the addict’s environment is pervaded with cues — reminders of the drug that cause the release of dopamine and predict a reward. This kind of learning is called behavioral conditioning, and the result is sometimes called cue-induced craving. It works even if the addict knows that a reward is not really coming because the capacity for self-control has weakened. The frontal cortex has become less effective at incorporating the information it needs to make decisions and judge the consequences of actions.

A small dose of the drug itself is one effective cue: “It’s the first drink that gets you drunk,” as addicts learn in Alcoholics Anonymous. Other conditioned stimuli are, to cite Alcoholics Anonymous doctrine again, “people, places, and things” associated with the drug. An addicted animal will resume taking the drug when it is returned to the cage where it first developed the addiction. In human beings, the signal could be the sight of a crack pipe or needle, a familiar bar, the presence of drug-using companions, or recurrent feelings of anxiety, anger, and sadness.

Reshaping neurons:

Research shows that addiction involves many of the same brain circuits that govern learning and memory — especially transmission involving the excitatory neurotransmitter glutamate. Addictive drugs can alter the responsiveness of neurons to glutamate for days, and repeated use sensitizes the brain’s glutamate receptors to the drug.

It’s becoming clear that neurons (brain cells) themselves change in the course of addiction. Long-term memories are formed by the activity of transcription factors — substances that switch on the genes that manufacture proteins, establishing new and strengthening old neural connections. All rewards increase the concentration of the transcription factor delta FosB in the nucleus accumbens. An excess of this transcription factor can heighten the risk of relapse in addicts long after they have stopped taking the drug. Even after levels return to normal, addicts may remain hypersensitive to the drug and the cues that predict its presence, possibly because delta FosB has caused neurons to sprout more of the (branches) dendrites that receive signals.

The new understanding of addiction comes mostly from animal experiments and brain imaging studies. Applying these results to complicated human situations can be tricky. In practice, drugs rarely have overwhelming powers. Most drug users do not become addicted, and those who do are usually burdened by special conditions and circumstances. Some develop impulsive and compulsive behavior because of weakening control by the frontal cortex. Antisocial and borderline personality are important risk factors for addiction. Deficits are found in the structure and activity of the frontal cortex in people with antisocial personality.

Others succumb to internal or external stress, which revives the memories that lead to relapse. Withdrawal from an addictive drug activates receptors for the stress hormone corticotropin-releasing factor (CRF) in the amygdala. Addiction often follows the stress of depression, schizophrenia, and other psychiatric disorders.

According to twin and adoption studies, heredity accounts for about 50% of individual differences in vulnerability to drug addiction. Scientists are exploring the effects of genes that provide the recipe for transcription factors, dopamine receptors, CRF, and catechol-o-methyl transferase, an enzyme that breaks down dopamine. One study has found that a high level of a certain type of nerve receptor (dopamine D2) provides some protection against alcoholism in a family that is otherwise genetically vulnerable. The influence of genes may be different at different stages — starting drug use, moving to regular use, addiction, and relapse.

Economic and cultural conditions can also affect the likelihood that implicit memories will take command. A person who lacks other strong interests, sources of satisfaction, and ways to solve problems is at greater risk for addiction.

Wider applications:

Researchers are only beginning to explore the differences and similarities between drug addiction and other consuming habits. It is possible that drug addiction differs only in degree from “addictions” to television, shopping, computer games, or even biologically natural rewards like food and sex. The formation of these habits is not as well understood as the roots of drug addiction, because animal models are more difficult to use, and the symptoms are less clearly defined. But common learning and memory pathways may be involved. Already there is evidence that compulsive gamblers think and feel like alcoholics or cocaine addicts. In thrall to memories of past wins, they cannot stop playing even when they know they will lose. In imaging studies, the brain of a gambling addict responds to the sight of a gaming table in the same way that the brain of a cocaine addict responds to a line of white powder or a crack pipe. New insight into all motivation, desire, and habit formation may emerge from research on drug addiction.


Knowing more about how addiction works in the brain has not yet given us any strikingly effective new treatments, but it has suggested new possibilities while providing a better understanding of how the available treatments work.

Today, two drugs are widely used to treat addiction, chiefly to alcohol and heroin — naltrexone, which blocks the effects of these drugs, and acamprosate, which may act on glutamate receptors. Both are modestly effective at best.

The National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism are supporting studies on more than a hundred experimental addiction medications. These medications may dampen the conditioned cues that perpetuate longing for the drug, restore glutamate regulation, normalize dopamine function, or influence CRF. Some day there might be chemicals that prevent transcription factors like delta FosB from acting on genes to cause permanent deleterious changes in neurons. The hardest job will be finding substances that lower the risk of addiction but do not interfere with responses to natural rewards.


National Institute on Drug Abuse

Medscape Addiction Resource Center

American Society of Addiction Medicine


Empower Community Health

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