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Addiction — 40 years later
Rockefeller's Mary Jeanne Kreek looks back on four decades of groundbreaking research into how illicit drug use impacts — and alters — the human body
BY CATHY YARBROUGH
It was a daring new research study that brought Mary Jeanne Kreek to Rockefeller University 40 years ago. During her medical training at NewYork Hospital–Cornell Medical Center, Kreek joined a project that challenged the then common notion that people addicted to heroin were immoral or behavioral deviants.

Along with Vincent P. Dole, who directed the landmark study, and Marie Nyswander, a psychiatrist who joined Dole at the same time, Kreek suspected that addicts may be victims of their biology, not their personalities. Their bold research pioneered the use of methadone in the chronic, or long-term, treatment of heroin addiction and established its medical safety and effectiveness for treatment to relieve a heroin addict’s hunger for the drug — a major reason for relapse. They proved that methadone could prevent heroin from exerting its powerful effects on the brain, and years later at Rockefeller, Kreek led the research team that identified multiple genetic variants for the site of action on brain cells where heroin exerts its influence.  Among the variants that she identified was a functional one with distinctly different activity from the normal gene.

When she joined the university in 1964, Kreek was participating in the first research elective that Rockefeller ever offered to Cornell medical residents. Today, Kreek, the university’s Patrick E. and Beatrice M. Haggerty Professor, heads the Laboratory of the Biology of Addictive Diseases. To mark the 40th anniversary of the inception of the university’s landmark addiction research, Rockefeller University Scientist spoke with Kreek.

Is research on addiction taken more seriously today than it has been in the past?

Yes, most scientists, particularly neuroscientists, do not doubt that addiction is a disease, and it’s a disease of the brain. The research evidence comes from molecular biology, neurochemistry and genetics, as well as basic clinical and treatment research. This research has shown that alcohol, cocaine, heroin and other drugs of abuse can change the human brain in predictable ways, and that these changes contribute to the behaviors that we identify as addictions.

What’s enormously exciting to scientists such as myself is how much we are learning today about the neurobiologic basis of how each of the specific addictions develops. This research will suggest effective approaches to early intervention and prevention as well as treatment.  

You speak of addictions, plural. So there’s not just one addiction?

Correct. Research has revealed many similarities — but also profound differences — in the ways that the various drugs of abuse act in the brain. For instance, heroin acts only at one site in the brain, the mu opioid receptor of brain cells. In sharp contrast, cocaine acts at three similar but different sites.

Does that mean that cocaine addiction is more complex than heroin addiction?

That’s actually a provocative way of putting it. It’s not really a more complex addiction, but the multiple sites of cocaine’s action in the brain complicate the search for a single pharmacological treatment that will be as effective against cocaine as methadone has been for heroin addiction. In fact, the lack of a single treatment that is effective against each form of addiction is really profound, direct circumstantial evidence that these drugs of abuse cause different forms of addiction, at the level of brain cells.

When you worked on the methadone studies in the 1960s, no one could know where methadone was acting in the brain?

No, we could not be at all sure of where it was acting.  However, our laboratory hypothesized the existence on cells of specific binding sites, or “receptors,” for heroin and its major metabolite, morphine. Further, we hypothesized that methadone would act at those same sites, and that its presumed and later proven long-acting qualities in humans would allow it to normalize the functions disrupted by the short-acting heroin. However, it was not until 1973 that three different research groups identified the specific cell receptors for opiates, which include heroin. We later found that there are three different kinds of opiate receptors and in the early 1990s the genes for these receptors were cloned. In 1994, our collaborator, Lei Yu, first cloned the mu opioid receptor gene, the site of binding of heroin and also methadone. We then identified five genetic variants, each containing the DNA code for the mu opioid receptors, the major molecular site for the action of heroin, and also methadone, in the brain. Two of these mu opioid receptors occur frequently — 10.5 percent and 6.5 percent — in the human population. Two years ago, my lab published a paper showing that some people who inherit a “high output” version of another opioid gene that makes the brain opioid peptide dynorphin, a neurotransmitter that is part of the brain’s pleasure circuit, may be less likely to fall prey to the addictive powers of cocaine. So that’s good news that we’re pursuing in ongoing research.

Are people genetically prone to addictions?

There’s a genetic component to each of these addictions. The genetic factors contribute 30 percent to over 50 percent of the relative risk to develop addictions. A colleague at another institution found that heroin has the largest relative risk on a genetic basis — 54 percent — and probably has more unique genes contributing to this risk.

Do your genes excuse you from having an addiction?

No. But they contribute to it. That’s why it’s inaccurate for anyone to argue that people with addictions to alcohol, cocaine, heroin or other drugs of abuse have “brought it on themselves.” Hypertension, diabetes, obesity and addiction are among the many diseases that are due to combinations of internal and external environmental factors as well as genes.

How powerful are genetics?

Epidemiological studies of drug use and addiction over the last 50 years in the U.S. and Europe have found that about one in three to one in five people who ever self-expose  — willingly inject or ingest heroin — will develop an addiction to it. One in 10 to one in 20 people who self-expose to alcohol become alcoholics. With cocaine, about one in 10 who self-expose to this drug will become addicted to it. These numbers are true in the United States, China and Europe. No country is immune to drug addictions.

Your studies revealed for the first time that people who were once addicted to drugs of abuse do not respond well to “stressors” — and those could be, I suppose anything from a traffic jam to being fired?

At the level of their brains’ neuroendocrine systems, both active drug-using addicts and former addicts who are no longer using drugs of abuse were found by my lab to respond atypically to stress. Their abnormal response, likely a product of the interplay of their genes and their environment experiences, may help explain why people become addicted in the first place, as well as why they are prone to relapse. The mu opioid receptor, which is the target of heroin, plays a major role in our body’s stress response system, especially in the hypothalamic-pituitary-adrenal axis.

And, your studies related to HIV and AIDS?

In 1984, my lab contributed to a crucial paper related to the then new disease that we now know as AIDS. In studies of blood samples from anonymous volunteer research subjects with addiction coming in for neurobiological or treatment research studies in my addiction research service at the Rockefeller University Hospital, we found evidence of the HIV antibody in 60 percent of untreated street heroin addicts. But importantly, only nine percent of former addicts who had entered an effective methadone program prior to 1978, when the AIDS epidemic hit New York City, and who had remained in treatment through the time of our study in 1985, had the antibody.

Why do you use “bidirectional” to describe your addiction research?

We perform research both at the laboratory bench and at the Rockefeller University Hospital with volunteer subjects, including both active addicts and former addicts in effective treatment, as well as healthy control subjects. Our work at each influences the other. The addiction research in the 1960s began with studies of patients in the hospital, but that work inspired many different basic research studies at the bench, in the lab. What we’ve learned in the lab has led to basic neurobiological studies in humans. In parallel, observations made in humans with addictive diseases have led to our development of novel animal models, which allow us to conduct more meaningful studies of the neurobiology, neurochemistry and behavior related to addictions in rats and mice.

For instance, the “binge” animal model that we developed to study cocaine addiction in rodents in the lab was based on our observations of people’s patterns of use of this drug. People also “binge” on alcohol, so our lab uses the “binge” model in rodent studies of alcoholism. People do not “binge” on heroin — it’s intermittently used, so our animal model studies mimic that pattern. For cocaine and alcohol, the “binge” model has been a more reliable way of learning how drugs can act as DNA switches turning genes on or off. In lab animals, for instance, “binging” on cocaine reduces the binding at the cell receptors for dopamine, one of the neurotransmitters that cocaine increases in the brain and that is part of the brain’s pleasure circuit. “Binging” on cocaine also increases gene expression and the numbers of mu opioid receptors, but with no increase in the neurotransmitter, beta-endorphin, which is commonly associated with the “runners’ high” as well as pain relief. Other opioid gene products, the dynorphin peptides, reduce the levels of dopamine. If those changes persist for a long time, which we have shown does happen, it could lay the basis for relapse as an addict tries to compensate for a crippled pleasure circuit.

SIDEBAR: Treating alcoholics, one at a time

November 19, 2004



 

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