by Rebecca Kolberg

Gazing out a window at the blue of the Chesapeake Bay framed by the steely glint of shipping cranes and the arch of a distant bridge, NIDA's intramural research center in Baltimore seems a world apart from NIH's main campus in leafy, land-locked Bethesda.

And in some ways -- its unique historical tradition, its self-contained camaraderie, and even its plentiful parking -- NIDA's intramural research program does stand alone. But when it comes to its scientific endeavors, there may be far less distance between NIDA and other intramural research programs than many scientists realize.

"The general progress of science has provided lots of new ways to explore drug addiction. But, to flip it around, the field of addiction research is also able to contribute to the kind of science of interest to broad parts of the neuroscience community and the NIH scientific community," says NIDA's Acting Scientific Director George Uhl.

Noting that epidemiological evidence indicates that "an incredibly large chunk" of U.S. morbidity and mortality, perhaps as much as 50 percent, may be related to behaviors driven by much the same kind of motivation-reward circuits that drive drug abuse, Uhl says NIDA scientists may be able to help others in the NIH intramural community understand some of these behaviors.

NIDA researchers may also be able to provide some valuable clues in the effort to solve a major neuroscience riddle: how memory works. "By my definition, addiction is a fairly specific form of memory ... a behavior that at some time depends on recalling your past experience with that drug," Uhl says. "Because we now know quite a bit about how drugs work on the brain acutely, at both the pharmacologic and the molecular level, we are actually in a good position to help contribute to questions about long-term information storage in the brain, which really is at the core of `memory' processes."

Sixty Years of Science

The forerunner of NIDA's intramural research program, the old "Narcotic Farm" in Lexington, Ky.

Although NIDA has only been part of NIH since 1992, its intramural research program traces its roots to the Research Division of the U.S. Narcotics Farm in Lexington, Ky. The 1,200-bed facility, often referred to as "Narco," was established by the U.S. Public Health Service in 1935 for the treatment of opiate addicts. In 1948, Narco's Research Division was renamed the Addiction Research Center (ARC) and placed under the jurisdiction of NIMH's intramural program. In 1973, NIMH's parent agency, the Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA) established NIDA. ARC was physically moved to Baltimore in 1979 after a nationwide ban on the use of federal prisoners as research subjects made it difficult to find patients for clinical studies in Kentucky. When ADAMHA's research programs became part of NIH three years ago, ARC -- which is now synonymous with NIDA's intramural research program -- came along as part of the package.

"When we [NIDA] were within ADAMHA ... there were competing voices. There was a focus on scientific rigor, but also a focus on the provision of service -- something that was split off when the Substance Abuse and Mental Health Administration was created," Uhl says. "Moving just the research components of the institute into NIH has really focused the energy on research."

NIDA Director Alan Leshner notes that even though the intramural research program represents only 5% to 6% of NIDA's total budget, it still represents the largest scientific research center dedicated to drug addiction. "Although by NIH standards it is small, by world standards on drug-abuse research, it is a central focal point," says Leshner, observing that very few academic institutions have the resources or the continuity of personnel for the types of long-term drug-abuse studies that ARC has been able to pursue.

Approximately 85 scientists currently work at ARC, which is located atop a hill at Johns Hopkins University's Bayview Campus in southeastern Baltimore, less than an hour's drive from the Bethesda campus. All six branches of NIDA's intramural research program -- molecular neurobiology, neuroscience, preclinical pharmacology, clinical pharmacology, etiology, and treatment -- are contained in ARC's 60,000-square-foot building and two nearby buildings. In addition to basic research labs, the facilities house 30 inpatient research beds in a closed unit, an outpatient research unit, and an 80-slot outpatient methadone clinic.

Research Outlook

Recent achievements by NIDA intramural investigators reflect how NIH affiliation has helped to reinvigorate its research outlook. Following up on pharmacologic leads uncovered by former ARC Director William Martin in the 1970s, Uhl, Jia Bei Wang, and their colleagues in 1993 succeeded in cloning the gene that encodes one of the major subtypes of opiate receptors, the u morphine-preferring opiate receptor, and in subsequent studies, went on to explore the protein's structure and function. Similarly, fueled by the ground-breaking pharmacologic research of NIDA's Michael Kuhar and Steven Goldberg, Uhl and Shioshi Shimada, with help from Kuhar, cloned the gene for the cocaine-sensitive dopamine transporter -- a so-called receptor that, when exposed to cocaine, blocks dopamine re-uptake in the mesolimbic pathways, initiating a series of events thought to cause the euphoric and rewarding effects associated with cocaine use.

On the preclinical and clinical front, intriguing current research at ARC includes Edythe London's positron emission tomography (PET) studies on the physiological basis of cocaine craving [see Commentary, page 10], Xiao Bing Wang's research using the differential-display method to examine gene-expression patterns in the brains of animals exposed to drugs, Goldberg's attempts to create transgenic mouse and nonhuman primate models that mimic the long-term changes observed in the brains of human drug abusers, Jack Henningfield's work on the psychological basis of drug craving and its utility in treatment, and David Gorelick's studies on the relationship between the rate of cocaine administration and euphoria. Early findings suggest that a slow-release, cocaine-like compound could possibly be used as a methadone-like treatment for cocaine addiction.

Tracking the history of ARC's research, Uhl says the emphasis has moved from finding out what happens to addicts when they take drugs to using animal models for self-administration to predict which drugs will be abused in humans, to working on defining which molecular sites were involved in this drug reward, and then on to finding the genes that encode such sites. "That's a fairly impressive progression compared with what's known about the biology of many disorders that involve behavior. ... Clearly, our challenge now is to try to have the same impact upon our understanding of the addiction, the use of drugs over the long term."

Life in Baltimore

Working with Uhl to explore the long-term effects of drug abuse on molecular events in the brain is David Vandenbergh, a senior staff fellow in the Molecular Neurobiology Research Branch. Like many of his colleagues, Vandenbergh says he makes
it to only the most interesting seminars in Bethesda because of time demands. Although he blames NIDA's remoteness for difficulties in renewing his NIH library card and getting supplies delivered from the NIH stock room, Vandenbergh says he doesn't consider being located in Baltimore a handicap. "Doing science is fairly similar no matter where you are," he says.

Amy Hauck Newman

Among the NIDA researchers who have spent time in Bethesda is another senior staff fellow, Amy Hauck Newman, a medicinal chemist who designs and synthesizes novel compounds to discover mechanisms underlying drug abuse. Before moving to Baltimore in 1990, Newman spent three years as a postdoc at
NIDDK, where she maintains collaborations with her mentor, Kenner Rice, and Anthony Basile on projects centering on dopamine transporters and opiate receptors. She is also working with NINDS' Michael Rogawski and Swami Subramaniam on studies involving N-methyl-D-aspartate (NMDA) receptors and potential anticonvulsant agents.

"The biggest advantage of being in Baltimore is space -- and no problems with parking!" Newman says. "I also find it very interesting to work in one building where a whole spectrum of scientific backgrounds are focused toward just one mission." However, Newman does miss the convenient access to the NIH library, interactions with other chemists, and ease of attending seminars in Bethesda. "I feel somewhat isolated now."

Peter Johnson, who came to ARC in 1993 as a Pharmacy Research and Training (PRAT) fellow and is now a staff fellow, says he would have wanted to work at NIDA no matter where it was located. "Drug-abuse research was the area where I wanted to go in my career ... and this is one of the world's premier institutions in that field," says Johnson, who is now studying opiate receptors and signal transduction within the cell.

Staying in the Loop

To keep intramural researchers at outlying campuses "in the loop," Newman advocates increased teleconferencing or videotaping of major lectures; continued improvements in e-mail service, which just became available to many ARC scientists last August; and occasionally moving some events from Bethesda to other campuses. "Not being forgotten is what's important," she says.

NIDA Director Leshner agrees: "Many people on the [Bethesda] campus are not familiar with the absolutely incredible resources available in Baltimore. ... There are lots of opportunities for collaboration that are going untapped." NIDA particularly welcomes collaborative partnerships involving PET, Leshner says, noting that ARC is one of the few research institutions in the world to have its own dedicated PET scanner. In fact, there is an interesting story behind the funding of that PET scanner. Leshner says the millions of dollars of equipment necessary for PET studies came from the federal government's sale of cars, boats, real estate, and other ill-gotten gains confiscated from convicted drug dealers.

NINDS' Rogawski says that more than distance may underlie the reluctance of some intramural researchers to collaborate with NIDA. "One of the problems is that some people may have an outdated perception that drug abuse research is soft science, not realizing that the field is now at the cutting edge of molecular, cellular, and behavioral neuroscience," he says, adding that Newman's scientific expertise in medicinal chemistry -- a relatively rare expertise at NIH -- has been a "valuable asset" to his studies.

Stephen Heishman, a NIDA research psychologist, says that currently, his only interinstitute collaboration is with a scientist who's already very familiar with NIDA's resources, Herb Weingartner of NIAAA -- an institute that was part of NIDA when it was originally founded. In their clinical studies, Heishman and Weingartner are examining cognitive functioning in polydrug users. Their preliminary findings show that compared with non-abusers, substance abusers not under the influence of any drug effect give two to three times more wrong answers when asked to recall a list of 12 nouns presented to them 20 to 30 minutes earlier. It remains to be seen whether this deficit in reflective processing -- the inability to "inhibit" wrong answers -- stems from drug abuse or is a predisposing factor for drug abuse, Heishman says.

Echoing the views of others at NIDA, Heishman says he finds that he's more inclined, given ARC's history and location, to set up collaborations with scientists at Baltimore medical schools -- Johns Hopkins and the University of Maryland -- than with NIH scientists in Bethesda. And like a substantial number of his colleagues, Heishman also enjoys the opportunity to teach at Johns Hopkins, where he is an assistant professor in the Department of Psychiatry and Behavioral Science.

Best of Both Worlds?

Jean Lud Cadet

Although NIDA's Baltimore campus, with its proximity to poor, inner city neighborhoods, is well-situated for recruiting drug-using volunteers for inpatient studies, its urban location and long-standing reputation as an addiction-research center inhibit the recruitment of middle- and upper-class drug users for outpatient studies, says Jean Lud Cadet, head of the Neuroscience Branch's Molecular Neuropsychiatry Section. Cadet says he is exploring the possibility of establishing a NIDA outpost at the Clinical Center in Bethesda for such studies.

Cadet, who spent time at the Clinical Center as a medical student and at NIMH as a medical staff fellow, says he also would like to see more exchange of scientific ideas among what he considers to be NIH's four neuroscience institutes: NIDA, NIAAA, NIMH, and NINDS. For example, no one from NIDA is currently part of the Neurosciences Working Group. "Sometimes it feels like that old saying `Out of sight, out of mind.' A lot of the clinicians and basic scientists in Bethesda don't know a lot of the people here -- and we have some really superb scientists," says Cadet.

For his part, Cadet works hard at maintaining his ties to the Bethesda campus. Drawing on what he's learned in copper-zinc superoxide dismutase (CuZnSOD) transgenic mice, which have shown resistance to the lethal effects of some methamphetamine drugs that affect the mono-aminergic systems of rodents, Cadet is collaborating with NIMH's Dennis Murphy and Anne Andrews on a preclinical study assessing the toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) analogs in the CuZnSOD mice. The hypothesis is that SOD will counteract the neurodegenerative effect of the MPTP analogs. "I don't mind driving 45 minutes if there's somebody I really need to talk to," he says.

Contact with colleagues in Bethesda has given Cadet a greater appreciation of Baltimore's relatively spacious labs and its lower labor costs for support staff. However, Cadet says his visits also underscore what he misses about the main campus: the ability to exchange ideas with scientists from a wide range of disciplines by simply walking down the hall or slipping into a seminar. "It's exciting to be in Bethesda. I get so stimulated when I go there that I end up thinking, `I wish I were here,'" Cadet says. "But after an hour or so, I come to my senses, and realize that, over the long-term, for what I want to achieve, it's better for me to be in Baltimore."

NIDA Intramural Research at a Glance

George Uhl

Contact: Acting Scientific Director George Uhl
Phone: 410 550-1538
Location: Addiction Research Center building, Johns Hopkins Bayview Campus, 4940 Eastern Ave., Baltimore, MD 21224.
Resources: Dedicated PET facility available for collaborations with the entire NIH intramural community. Special expertise in systems for assessing reward-behavior phenotypes in transgenic mice and other animals. Secure inpatient unit for studies involving patients who abuse drugs.

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