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National Institute on Drug Abuse -  NIDA NOTES
Special Report:
ARC's 60th Anniversary

Volume 10, Number 6
November/December 1995

NIDA's Addiction Research Center (ARC) 60th Anniversary

Molecular Pharmacology, Brain Scans, and Human Attention Spans

By Robert Mathias & Neil Swan, NIDA NOTES

The Neuroscience Branch's three sections conduct research into the effects of drugs on the brain. Some researchers study receptors, the molecular sites where drugs bind, to determine the receptors' role in drug-induced euphoria and drug craving. Other scientists study and use brain scans to show how drugs influence the brains of living animals and human volunteers.

The Molecular Pharmacology Section, headed by Dr. Michael J. Kuhar, conducts advanced molecular studies of the actions of drugs, particularly cocaine. Dr. Kuhar, who is also chief of the Neuroscience Branch, says that DIR scientists represent one of the world's leading research efforts in the development of medications and ligands, or binding partners, for receptors for cocaine and other drugs. Scientists also develop techniques for conducting molecular biological studies of how cocaine works. Their goal is to find substances that bear promise as potential cocaine blockers or medications.

The section has studied more than 350 analogs - or chemical cousins - of cocaine. Many of these cocaine analogs are highly selective, both in discerning specific brain binding sites and producing a variety of effects. The selectivity and varying effects of these analogs are keys to understanding and controlling how cocaine works.


Dr. Jean Lud Cadet uses a laboratory instrument to amplify
DNA to help determine the effects of drugs on human memory
and attention span.

The section's molecular research also focuses on the role of the dopamine transporter, which is involved in producing cocaine's distinctive pleasurable "rush." Through radioactive tagging and brain scans, the actions of various cocaine analogs in the brain are converted to images and then digitally recorded by computers.

This use of molecular chemistry to develop and test cocaine analogs, combined with brain imaging and physiological and psychological studies of the effects of these unique compounds, results in the hybrid science sometimes called molecular pharmacology.

Already the section's research has had a serendipitous benefit: the discovery of a compound, RTI 55, that has significant potential as an imaging tool for diagnosing Parkinson's disease.

Another unit of the branch, the Molecular Neuropsychiatry Section headed by Dr. Jean Lud Cadet, a psychiatrist and neurologist, studies the effects of prolonged drug use in humans and animals.

Current research with humans centers on long-term effects of the use of cocaine, heroin, and methadone, a treatment medication for heroin users. Volunteers, recruited from among people identified as having been cocaine users for at least 2 years, live drug free for 30 days in the ARC's 26-bed residential ward. These volunteers are medically and neurologically evaluated when they enter the ward and again when they leave drug free a month later. Tests seek evidence of improved neurological function at the end of the 30-day residential period. Following the studies, volunteers are offered drug abuse treatment.

Dr. Cadet uses a battery of neurological tests to determine the effects of drugs on human memory, attention, and decision making. Tests of the cerebral vascular effects of cocaine are performed because of concern about the prevalence of strokes among young people who use cocaine. Preliminary data suggest that, after drug abstinence, there might be an improvement in the subjects' ability to maintain their attention spans on a specific concept for longer periods of time, says Dr. Cadet.

The section uses mice as models to study the long-term toxic effects of amphetamines. After prolonged daily use by humans, amphetamines, like cocaine, can produce a psychosis similar to acute schizophrenia. To study the causes of this drug toxicity, researchers use two strains of mice: one that is vulnerable to and another that is protected from the toxic effects of amphetamines.

The Neuroimaging and Drug Action Section uses noninvasive imaging, or PET (positron emission tomography) brain-scanning techniques in human volunteers, and x-ray images of radioisotope tracers in animals, to better understand the mechanisms of drug action and how drugs influence brain functions.

Molecular biological studies are probing the way
that cocaine works, seeking substances that might
be used as cocaine blockers or medications.

Since 1983, DIR researchers have used these and other scanning techniques to study the acute effects of drug abuse in human volunteers. A key finding - that drugs of abuse reduce the brain's use of glucose, its main source of energy - led to continuing studies and "mapping" of drug-influenced brain functions.

More recently, researchers began using PET scans to study the patterns of brain metabolism related to long-term use of drugs. Chronic drug abusers - compared with nondrug users of the same age, gender, and education level - appear to have deficits in the visual-association cortex area of the brain. "This appears to be a part of the brain that is involved in decision making. It is involved particularly in making choices between behavior that is associated simultaneously with reward and the risk of harm," explains Dr. Edythe D. London, section chief.

Dr. London and her colleagues are now preparing imaging studies to try to determine whether people who are not drug abusers but who have conditions associated with increased frequency of drug abuse, such as antisocial personality disorder (in adults) and conduct disorder (in children), are more prone to drug abuse than individuals who are not afflicted with these disorders, says Dr. London.

The ARC brain scanning facility's capacity was expanded recently with the installation of a new state-of-the-art PET scanner that can produce brain images with greater detail and clarity. The Siemans high-resolution scanner is the only such device in the world devoted exclusively to drug abuse research.

From NIDA NOTES, November/December, 1995

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