Still, while we celebrate the

A Campaign Concludes

ne of the most satisfying

and all it will continue to make pos

duties during my year as

sible, many challenges remain. Our

interim dean was observing

the wonderful progress made by the

because there are always fund-rais-

School of Medicine’s capital cam

ing needs in an institution as large,

paign. The Creating the Future of

complex, and forward-looking as

Medicine campaign was launched in

ours. Our new executive vice presi

the fall of 1995, and it was my plea-

dent and dean, Dr. Arthur Ruben-

sure to preside at an event this past April that celebrated its official close. There was indeed much to celebrate. The total raised in those five years is a tribute to all our donors and volunteers: $648 million for education, research, and patient care. We had an amazing 42,000 donors, and the average gift was about $14,000. Among alumni, the average gift was $8,469. I am happy to point out that Penn medical alumni have always answered the call for support during capital campaigns. We can trace this support back some 130 years, when a young clinical lecturer named William Pepper Jr. led alumni in a three-year campaign to raise $700,000 to establish the Hospital of the University of Pennsylvania.

Recruiting and retaining the finest faculty has long been a priority at Penn. As the Ruth Wagner Van Meter and J. Ray Van Meter Professor Emeritus of Neurology, I know at first hand how valuable the support provided by endowed chairs is to our faculty members. In the course of the campaign, 45 endowed chairs were created in the school.

The endowment for financial aid showed an astonishing growth: from $37 million in 1989 to $127 million in 2000. One reason for the increase is that student financial aid was one of the campaign’s priorities – but in addition, the School of Medicine had several alumni and friends who served as champions of financial aid. Two couples deserve special mention, the Gambles and the Welshes. Raymond H. Welsh, a trustee of our Health System and a 1953 alumnus of the Wharton School, chaired the entire campaign. In addition, he and his wife, Joanne, launched the Welsh Faculty Challenge, by which they matched every gift of $1,000 or more from a member of the faculty, up to a total of $1 million. In all, the Faculty Campaign Committee helped to secure gifts from more than 250 faculty members in support of student financial aid. Including matching funds put up by the Welshes and by Walter J. Gamble, M.D. ’57, and Anne Gamble, close to $4 million was generated by faculty giving. It was an honor for me to serve as chair of that committee.

No overview of the capital campaign would be complete without a salute to the Gambles. They created the visionary Twenty-First Century Endowed Scholars program to relieve the increasing debt burden shouldered by most medical students. After their initial gift of $10 million to create full-tuition scholarships, they have continued over the years to support financial aid through gifts of an additional $17 million. For example, they established the Gamble Challenge to alumni donors at the $25,000 level, and 58 alumni responded.

Albert M. Kligman, M.D., Ph.D., is both an alumnus of the School of Medicine (Class of 1947) and an emeritus faculty member in our Department of Dermatology. He and his wife Lorraine H. Kligman, Ph.D., pledged $1 million in support of the Twenty-First Century Endowed Scholars program. There are many other supporters, too numerous to name here, but all of them have our profound thanks.

I would also like to thank the Campaign Steering Committee, including members from our Health System’s Board of Trustees, for providing essential oversight of the campaign, for keeping us on track, and for providing stewardship on special projects. Among our alumni, the National Alumni Council made great contributions to the capital campaign in terms of gifts, loyalty, and wise counsel. I want to acknowledge its tireless chairman, Stanley J. Dudrick, M.D.’61.

stein (see “Vital Signs”), will be setting the priorities in conjunction with Krista Mattox and her expert staff in the development office, but some needs stand out. A plan is under way to upgrade the school’s educational facilities and cluster them in the John Morgan Building and adjacent parts of the Anatomy-Chemistry Building. This is a major project, and there are others. We need better connections and access between the parts of the Health System on the old site of Philadelphia General Hospital and the rest of the medical campus.

In the area of health services, the operating rooms and the perioperative acute-care units have to be upgraded and expanded, particularly at HUP. Capital intensive upgrades are also necessary at Pennsylvania Hospital, Presbyterian Medical Center, and Phoenixville Hospital. Further, we have a desperate need for an ambulatory care center on campus. Another opportunity is to develop more comprehensive capabilities in the University of Pennsylvania Cancer Center; a particularly attractive possibility is a state-of-the-art proton-beam facility.

It is still too early to measure the full impact of the Creating the Future of Medicine campaign – by definition, the future lies ahead. But we are confident that the impact will be measured in new advances made in research, in the world-class physicians trained in our tradition of excellence, and in the number of lives saved and restored through our patient care. On behalf of this great institution, I extend my sincerest thanks to all who have contributed to our campaign to create the future of medicine.

UNIVERSITY OF PENNSYLVANIA MEDICAL CENTER / SUMMER 2001 VOLUME XIV, NUMBER 3

THE SCIENCE OF ADDICTION

IN THE STYLE OF HOUDON

A PHOTOGRAPH OF GOD?

CELEBRATING THE CLASS OF ’51

In his 30 years as director of Penn’s Treatment Research Center, Charles P. O’Brien, M.D.,

G.M.E. ’69 Ph.D., has witnessed changes in the way scientists understand addiction, thanks to advances in neurochemistry, neurophysiology, and genetics. Despite resistance among many who deliver treatment, the trend in research today is to focus on using medication to treat addiction.

When John A. Lanzalotti, M.D. ’75, found it increasingly difficult to make a living as a surgeon and physician, he was able to use his artistic talents and his skills at visualizing three dimensions to develop a business as a sculptor. His chief inspiration is Jean-Antoine Houdon, known for his busts of Franklin and other Founding Fathers.

In a new book, Andrew B. Newberg, M.D. ’93, and the late Eugene D’Aquili, M.D. ’66, Ph.D., reported on their quest to study spiritual experience through the latest techniques of modern medicine. Using a SPECT camera, they found that the human brain alters during intense contemplation such as Buddhist meditation and the prayer of Roman Catholic nuns.

The questionnaires returned this spring by members of the Class of 1951 suggest that many of them took the words of their old dean to heart: “If the demand for your services is great, your obligation to the community is correspondingly increased.” Fifty years later, these alumni have a record of achievement in many different areas.

DEPARTMENTS	EDITOR’S NOTE	Inside Front		LETTERS	4
	Saluting Bill Kelley
	VITAL SIGNS Mount Sinai’s Rubenstein is named new EVP, dean		2	ALUMNI NEWS It Happened One Weekend Progress Notes			28
	Gene therapy reverses blindness in dogs			THE LAST WORD		Inside Back
	A new tool for the era of proteomics			ACampaign Concludes

STAFF	JOHN R. SHEA, Ph.D. LEWIS & NOBEL DESIGN	Editor Design / Art Direction
ADMINISTRATORS	REBECCA HARMON MARCIA L. ROBERTS	Chief Public Affairs Officer Director of Medical Alumni Relations and Institutional Events
	Penn Medicine is published for the alumni and friends of the University of Pennsylvania Medical Center by the Office of Public Affairs. © 2001 by the Trustees of the University of Pennsylvania. All rights reserved. Address all correspondence to John Shea, Penn Medicine, 2018 Penn Tower, University of Pennsylvania Medical Center, Philadelphia, PA 19104-4385, or call (215) 662-4802, or e-mail john .shea @uphs.upenn.edu. Visit Penn Medicine’s web site: http://www.med.upenn.edu/prnews/publications/Penn_Medicine.shtml

VitalSigns

2 ■ PENN MEDICINE

Health System continues its financial recovery

lthough the final audited figures for Fiscal Year 2001 are not yet available, the University of Pennsylvania Health System continues to make progress in its financial recovery. Through the third quarter, ending March 31, 2001, UPHS had an operating profit of $24.0 million. That is a $34.8 million improvement over the corresponding period of the previous fiscal year. Given the Health System’s recent history – when it had close to $300 million in operating losses in FY1998 and 1999 – its showing for this current fiscal year appears all the more impressive. Nor has it gone unnoticed by Penn’s peer institutions, the bond-rating agencies, and the media. For example, in the February 5 cover story of Modern Healthcare, the performance by UPHS was characterized as a “dramatic success” story.

Arthur Rubenstein, M.B., B.Ch., the newly named executive vice president for the Health System and dean of the School of Medicine, praised the “outstanding job” done by Robert D. Martin, Ph.D., the CEO of the Health System. Said Rubenstein, “The turnaround has been amazing – truly amazing.”

Gene therapy reverses blindness in dogs

esearchers at Penn’s Scheie Eye Institute have developed a gene therapy protocol that successfully restored sight in dogs afflicted with a variation of Leber congenital amaurosis (LCA), a severe form of retinal degeneration that, in humans, renders infants permanently blind. The work was done in collaboration with researchers from Cornell University (who discovered the mutated gene in dogs) and the University of Florida (who helped establish the adeno-associated virus that served to deliver the necessary protein). The study appeared in the May issue of Nature Genetics.

Under optimum conditions, normal protein transports a Vitamin A-like compound to the retina, which is necessary for sight. In some cases of animal and human LCA, wild-type RPE65 – the protein that transports the necessary Vitamin A-like compound – is missing from the gene, which results in blindness.

According to Jean Bennett, M.D., Ph.D., associate professor of ophthalmology and a senior coauthor of the study, previous studies to reverse blindness in rodents have been successful, but this is

Jean Bennett, M.D., Ph. D.

Honoring Excellence

egun in the spring of 1997, the Awards of Excellence program is a way for the School of Medicine to recognize its most outstanding faculty members for their research and clinical achievements. This year’s Awards of Excellence dinner is scheduled for Thursday, November 15, at 6:00 p.m., in the lobby of Biomedical Research Building II/III. Tickets are $90.00. For more information or to attend, call Medical Alumni Relations at 215-898-5298. the first successful outcome using larger animals. “This study takes a great stride forward in demonstrating that gene therapy does not just slow down a retinal degenerative disease, but can actually provide recovery of vision to an animal that was previously blind,” said Bennett, a researcher at the F.

M. Kirby Center for Molecular Ophthalmology at the Scheie Eye Institute.

In the Penn study, researchers injected a recombinant adenoassociated virus (AAV) carrying wild-type RPE65 into the area between the photoreceptors and the retinal pigment epithelium of three dogs. After 90 days, an electroretinogram showed that the waveforms of the treated eye were similar in scope to those of a sighted dog's eyes. Behavioral testing four months later was consistent with the electrophysiological results. The treated dogs all avoided collision with objects in front and to the right (the side injected), yet they consistently collided with objects to the left. In contrast, the untreated dog did not avoid objects in any direction.

Albert M. Maguire, M.D., associate professor of ophthalmology and one of the co-authors of the study, told The Philadelphia Inquirer that a few early experiments had attempted to inject the protein directly into the eye. These met with marginal success, however, and a better strategy seemed to be to administer the gene that would allow the dogs to make the protein themselves – which is the essence of gene therapy.

Since the publication of the study and its resulting publicity, Bennett has received hundreds of calls and e-mails. She cautions that “we are nowhere near the introduction of the missing protein in humans to restore sight,” yet she is very optimistic about future developments.

The other researchers in the study are Samuel Jacobson, M.D., Ph.D. (Penn), Gregory Acland, V.M.D., and Gustavo Aguirre, V.M.D., Ph.D. (Cornell), and William Hauswirth, Ph.D. (Florida). Rosann G. Thompson

VitalSigns

Greene Eberwine

When we started the clinic, we had visions of it becoming both a community resource and an educational experience for students, perhaps integrated with the medical school curriculum. I agree wholeheartedly with the sentiments in Marie Gehret’s article that introducing students to this population in this setting early in medical school has very positive influences on their attitudes, clinical skills, and interpersonal skills. The clinic influenced the person and doctor I have become and provided the kind of care and education that my classmates and I sought when entering medical school.

In the first year we knew there wasn't time to accomplish all that we hoped but were elated to know that other students would follow, adding their own initiative to the clinic. It is extremely gratifying to see that the clinic has matured to be everything we dreamed and more, and that there is consistent faculty support to keep the clinic running. I want to applaud the hundreds of students and faculty volunteers who have individually and collectively contributed to something very unique for a community in desperate need of support. Well done. I am very proud of my Penn Med heritage and the legacy you have left for others to follow.

David A. Kregenow, M.D. ’95

Fellow, Pulmonary and Critical Care

University of Washington

BACK IN 1755

Neither your article or another one I read recently, perhaps in a Jefferson publication, mentioned the most fascinating item at Pennsylvania Hospital.

Protected by a wooden cover is the original cornerstone which speaks of the beneficence of George III in supporting the new hospital. I do not recall the exact text but it would certainly be worth publication all these years later.

Bernadine Z. Paulshock, M.D. ’51

Wilmington, Del.

The editor replies: The timeline for Pennsylvania Hospital that is found on the hospital’s website notes that the original cornerstone can still be viewed at the southeast corner of the East wing of the Pine Building. Instead of a wooden cover, it is now protected by a more contemporary Plexiglas cover. The text, drafted by Benjamin Franklin, acknowledges George II, who reigned until 1760. The text reads: “IN THE YEAR OF CHRIST MDCCLV. GEORGE THE SECOND HAPPILY REIGNING (FOR HE SOUGHT THE HAPPINESS OF HIS PEOPLE) PHILADELPHIA FLOURISHING (FOR ITS INHABITANTS WERE PUBLICK SPIRITED) THIS BUILDING BY THE BOUNTY OF THE GOVERNMENT, AND OF MANY PRIVATE PERSONS, WAS PIOUSLY FOUNDED FOR THE RELIEF OF THE SICK AND MISERABLE; MAY THE GOD OF MERCIES BLESS THIS UNDERTAKING.”

TRUTH VS. TRADITION?

Re: “The First Turns 250” (Spring 2001): As a Penn graduate (x 3) and as one who spent ten years in Philadelphia, I am well aware of the importance of The Pennsylvania Hospital and of colonial dates and events in the background of the city.

As a native of Louisiana, and as one who has spent his entire post-residency career in Louisiana, I have some pride in this state, also, and a wish that historical accuracy be acknowledged.

Charity Hospital of Louisiana at New Orleans was founded in 1736 and celebrated its 250th anniversary with great fanfare in 1986. Thus I take exception to part of the opening sentence which credits Pennsylvania Hospital as “the oldest hospital in the United States.” As “the colonies’ first hospital” – no question. But since Louisiana became part of the Union in 1812, the facts have been different for 189 years!

Let truth top tradition!

Isidore Cohn Jr., M.D. ’45

Chairman Emeritus,

Department of Surgery

Louisiana State University

The editor replies: Dr. Cohn’s letter raises again the question of primacy, which we visited briefly in our Summer 2000 issue when trying to determine which was the oldest hospital constructed by a medical school for teaching purposes (Editor’s Note: “Who Was First?”). Sources at Pennsylvania Hospital remain comfortable characterizing it as “the nation’s first.” The phrasing that troubled Dr. Cohn – “the oldest hospital in the United States” – is ambiguous, and was written perhaps too carelessly by me, not by writers at Pennsylvania Hospital. Yet “United States” is synonymous with “the nation,” a political entity, rather than with “America,” a geographic entity. One could argue, then, that Pennsylvania Hospital has been a United States hospital for 225 years and that Charity Hospital has been one for 189 years.

But whether Dr. Cohn is persuaded by this argument, the picture seems even more complicated than that. While conducting a search on the Internet, I discovered other claimants to the title of oldest hospital. In the San Francisco area, there is the Hospital San Juan of God, previously known as Saint John the Baptist Hospital. Its claim: founded in 1550. (As the web page oddly puts it, “Being also the oldest hospital in America that works in the same building of their foundation.”) The site for Bellevue Hospital in New York calls it “America’s oldest public hospital, which opened in 1736.” (Compare the ushistory.org description of Pennsylvania Hospital as “America’s oldest hospital.”) If we define America as North America, there is also a claimant in Quebec: the Ho^{^}tel-Dieu du Précieux Sang, founded in 1637, “the oldest hospital in North America.”

Taking the easy way out, the editor reserves judgment.

By Lisa J. Bain

6 ■ PENN MEDICINE Charles P. O’Brien, M.D., Ph. D., has served as director of Penn’s Treatment Research Center since its founding in 1971.

Addison Geary

INVESTIGATORS IN PENN’S DEPARTMENT OF PSYCHIATRY ARE TACKLING THE COMPLEX AND OBSTINATE PROBLEM OF ADDICTION FROM A VARIETY OF ANGLES. THEIR APPROACHES INCLUDE FINDING THE MOST EFFECTIVE DRUG TO DEADEN THE CRAVING, SEEKING TO UNDERSTAND THE NEUROANATOMY OF MEMORY AND DESIRE, AND STUDYING THE GENETIC LIKELIHOOD THAT AN INDIVIDUAL WILL BECOME ADDICTED.

he history of treatment for drug addiction has been a story of change and resistance to change. So says Charles P. O’Brien, M.D., G.M.E. ’69, Ph.D., professor of psychiatry at Penn. As director of Penn’s Treatment Research Center (TRC) since its founding in 1971, O’Brien has been a primary agent of that change. During his two years of service in the U.S. Navy during the Vietnam War, he treated soldiers returning to the States for a variety of illnesses, including many cases of heroin addiction. But he found no effective treatment to offer these veterans. Given his training in both neurology and psychiatry, O’Brien became particularly interested in the effect of drugs on the brain.

“While I was in the Navy, I used my own money and my Navy uniform and went around the country looking at the various programs that were in operation at the time,” he says, noting that the uniform allowed him to travel at reduced fares around the country. The results of his quest were discouraging. There was little research being done and little knowledge among clinicians that any research was under way. “So we designed a program that would have treatment and research together, so that we could study the treatment in an organized way and try to find out whether treatment A was better than treatment B.”

Federal funding was available because of the Vietnam War. “There was a tremendous hysteria about heroin addicts coming back to the United States,” says O’Brien. “That put a lot of pressure on us to develop treatment programs very rapidly.” At that time, the focus was on heroin addiction; cocaine was then very expensive and not widely available. But in the 1980s, the cost of cocaine dropped and crack cocaine became available, which allowed more efficient delivery of the drug to the brain. As the demographics of drug use changed, so did the TRC, not only in terms of what was treated, but how it was treated.

Throughout the decade of the ’70s, psychotherapy was the only available therapy and the results were not encouraging. In the mid ’70s, O’Brien and colleagues demonstrated for the first time that drug effects were conditioned, and studies began to focus increasingly on using medication to treat addiction. This trend in research continues today, despite continued resistance among many of those delivering treatment. Meanwhile, research into the neurochemistry, neurophysiology, and genetics of drug addiction has changed the way scientists understand addiction and has led to a new generation of drug treatments.

Today, O’Brien oversees addiction research and treatment involving about 40 investigators at three main clinical sites – the TRC at Penn, Presbyterian Medical Center, and the Veterans Affairs Medical Center – as well as a network of affiliates throughout the Delaware Valley where clinical trials are conducted. Everyone treated at the TRC participates in a grant-funded clinical trial. Most of the funding comes from the National Institutes of Health, and most of these trials are for the treatment of addiction to cocaine, alcohol, and nicotine.

Animal models reveal clues

One of the factors that has fueled the study of the science of addiction is the availability of animal models. In the late ’70s, Joseph R. Volpicelli, then an M.D./Ph.D. student at Penn, was interested in using animal models of psychopathology to study the relationship between stress and medical problems, particularly addiction. One question he pursued: Might stress somehow cause people to become addicted? Using foot shock to induce stress in rats, Volpicelli observed the effect of stress on the animals’ drinking behavior. “I was really surprised at the findings,” he recalls. “What I found was that rats drink alcohol not when they are really stressed, but after the stress is over. It was that finding that led me to reexamine the whole relationship between stress and drinking and why some people become alcoholics.”

In response to trauma, the body releases endogenous opiates called endorphins, naturally occurring brain chemicals that bind to opiate receptors in the brain. Binding of the receptors, whether by endorphins or by opiate-containing drugs such as heroin, stimulates the brain’s “pleasure centers.” Volpicelli theorized that when the stress is over the opiate level falls, resulting in an experience of letdown or withdrawal, and that alcohol stimulates the opiate receptors and compensates for the rebound withdrawal.

Although the results of the first naltrexone study were impressive, over time Volpicelli and others observed that people stopped taking the medication because they missed the high. “An important limitation of this whole endeavor,” he says, “is that you need to have the person motivated enough to take the medicine and want to get better for the medicine to work.” For their second naltrexone study, he and his colleagues designed a more personal psychosocial treatment, which he calls the “BRENDA” approach, to be used in conjunction with naltrexone. “It’s a more expensive approach but we think that since the results are so much better, it’s ultimately cheaper in the long run for society and even for insurance companies.” As

Training Doctors to Treat Substance Abuse

esistance to the idea that addiction is a chronic disease runs strong in American society. Nowhere is this more true than among medical professionals, according to Charles O’Brien, M.D., Ph.D. “People in practice practice the way they were trained,” he says. And what medical professionals in training are learning, he adds, is “very, very little.”

According to a survey conducted by the American Association of Medical Colleges (AAMC) in 19992000, only 5 of the 125 responding medical schools require a course in substance abuse. Most medical schools offer an elective or fold substance abuse studies into another required or elective course. At Penn, medical students are required to take a full course in addiction: 25 hours in the “brain and behavior” block of integrated neuroscience. One of the few such offerings across the country, it attracts students from other medical schools who come to Penn to take the course, spend time at the TRC, and learn more about addiction.

The course evolved gradually over the past 30 years. In the early 1970s, O’Brien recalls, a group of medical students approached him and said they would like to learn more about addiction. At that time, drug reactions were common on college campuses such as Penn, and a volunteer group of medical students made themselves available to talk to troubled undergraduates about their drug problems. But the “student doctors” did not know very much, so they asked O’Brien to teach them. The elective course O’Brien set up was very popular with students — “standing room only,” as he puts it.

Then, in the late ‘80s, the School of Medicine held a retreat to review the curriculum and invited several recent graduates of the school to talk to the faculty about what they felt they had missed in their training. Says O’Brien, “One the people get better, the treatment “keeps them out of hospitals, out of emergency rooms, out of needing liver transplants.”

In a third study, the team showed that the treatment could be delivered by nurse practitioners. More importantly, they showed that treatment over nine months rather than three months yielded better results. “It’s like the treatment of hypertension, diabetes, or asthma,” says Volpicelli. “You stop the medication and people’s symptoms come back. So it looks like alcoholism is like other chronic medical diseases in which you need long-term care as opposed to just going away for 30 days and expecting that people are going to get better.”

The neuroanatomy of desire

The pleasure centers of the brain that are tickled by alcohol are, of course, also activated by a host of other stimuli, from food

of the things they kept mentioning was that they all were seeing drug-abuse problems in their practices, and they didn’t learn enough about it in medical school because the elective was too brief” or the students failed to grasp the contents. As a result of that retreat, a full required course on substance abuse and addiction was squeezed into the curriculum.

Getting the course into the curriculum has not completely broken down the resistance among medical professionals to accepting addiction as a chronic disease. Kyle Kampman, M.D., reports that he is occasionally surprised, when giving a lecture on addiction, to hear the responses of some medical students – “that addiction isn’t really a disease.” That attitude, he says, is “part of the struggle.”

Yet according to O’Brien, the course on substance abuse has been effective in changing attitudes among many medical students. The problem, he notes, is and sex to cocaine and heroin. The centers are located in the limbic regions of the brain, which devel

that when the students go to the wards, they are influenced by their senior residents and the attending physicians, many of whom presumably have not taken the addiction course in medical school.

“I remember one medical student who came back to me after taking the course,” says O’Brien. “He was doing this medicine rotation and he said, ‘Dr. O’Brien, I had this patient who is an alcoholic with really severe liver disease and esophageal varices, and he was coughing up blood and everything. And so we treated all these problems, and I asked the chief resident if I could refer this patient to the alcohol treatment program. And [the resident] said, ‘I don’t believe in that.’ So, essentially, what could the student do? This is like saying, ‘I’m going to give people with pneumonia an aspirin to keep their fever down, but I’m not going to treat the bacteria that’s causing the pneumonia.’”

oped early in human evolution and have functions related to activities important to survival – eating, reproducing, and avoiding danger. Animal studies have identified certain areas in the brain that are especially important in this circuit. One of these is a small almond-shaped structure called the amygdala, found in the middle part of the temporal lobe of the brain. This is a “way station” that is critical for learning about reward or danger. Another structure involved in the circuit is called the anterior cingulate, which appears to be important in riveted attention and emotional reactivity. The amygdala, the anterior cingulate, and a third structure called the nucleus accumbens are part of a circuit that, says Anna Rose Childress, Ph.D., “enables the organism not just to experience the reward, the pleasure, or the danger, but to learn about it, so that they can get back to what they perceive to be the good things again or avoid the bad things.”

Childress, a clinical associate professor of psychology in psychiatry, has been using neuroimaging techniques in an effort to map out the neuroanatomy of desire. Her work began years ago as she tried to understand craving, a cardinal of the things we often heard from patients was that encountering

Neurons communicate with one another via neurotransmitters such as dopamine. When a neuron is stimulated, it releases chemicals called neurotransmitters, which cross the gap (called the synapse) between two neurons. The second neuron has receptors on its surface that bind the neurotransmitter. The binding of neurotransmitter to receptor may either activate or inhibit the post-synaptic neuron, depending on the specific receptor subtype and the neurotransmitter involved. Many neurotransmitters are involved in the brain’s reward pathway as well as in brain circuits that process emotions, learning, and memory. Different drugs affect these neurotransmitter pathways in different ways.

ed more than information about

the effectiveness of baclofen. The

medication was clearly helpful to

this patient in bringing his craving

into a manageable range. “He did

not feel literally pulled out of his

wheelchair to go look for cocaine,

as he did when he omitted

baclofen or before he was on it.”

Before the patient decided to stop

using drugs – which he did decide

during his stay at Presbyterian –

he was still “planning his life

around essentially a couple of

hours of cocaine pleasure at the

end of the month. So he wasn’t

driven by craving, but made a

conscious intellectual plan to

forego his baclofen knowing he

could have a few hours of plea

sure.” The lesson, asserts Chil

dress, is that reducing the craving

for drugs alone is not likely to be

enough for most people with an

addiction. Even if a drug reduces

cocaine craving quite a lot, it usu

ally will not perform what Chil

dress calls “a selective memoryec

tomy,” so that the person no

longer even remembers cocaine or

the high it brought. “The person

will still be in the role of making

an active decision of whether or

not to continue.” Investigators are also looking

at other neurotransmitters that

may play a role in addiction. “I

doubt very much that in some

thing as robust as addiction that

one neurotransmitter and one sys

tem is the whole story,” says Gary

Aston-Jones, Ph.D., professor of

psychology in psychiatry and of

pharmacology. In recent years,

several studies, including those

conducted by Aston-Jones and col

leagues, have focused on the role

of serotonin, a neurotransmitter

that interacts with many neuro

transmitter systems, including fond of Cocoa Puffs), or at the signal for cocaine, dopamine is released in what Childress describes as “little gushes.” Her plan is to use tracers in the brain that have an affinity for dopamine receptors. As before, she will show subjects the video with cocaine associations before doing a PET scan. If the subject’s brain releases dopamine while viewing the video, the dopamine will compete with the tracer for the receptors. The image will thus be a mirror image; if more tracer is imaged, it means there was less dopamine competing for the receptor.

Another way to ask the neurochemical question, says Childress, is to pretreat patients with a medication that modulates brain dopamine and then observe whether this pretreatment blunts cue-induced craving and the activation of the critical brain areas. Such medications may act either directly or indirectly on brain dopamine. For example, Childress has been interested in using this approach to investigate whether a muscle relaxant called baclofen might be effective in blunting craving. Baclofen works on the brain’s GABA (gamma-aminobutyric acid) system. GABA is one of the most prevalent neurotransmitters in the brain. Animal studies have shown that medications of this type affect many cocaine-related behaviors: for example, they reduce the animals’ enthusiasm for taking cocaine and block their preference for a location in which they previously received coca