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Cocaine Studies Reveal New Medications For Addiction; How Brain Regulates
Hunger

NEW ORLEANSResearchers at the Yerkes Primate Center of Emory University
have synthesized a compound that shows promise as a medication for people
addicted to cocaine and amphetamines. Currently there is no treatment to
help the millions of Americans who abuse these drugs. In related cocaine
studies, the scientists also discovered that food intake in animals is
controlled at least in part by a new group of neuropeptides, which may be
useful in developing treatments for eating disorders such as obesity and
anorexia.

These and other studies by Yerkes scientists describing the neural pathways
involved in cocaine addiction were presented this week at the annual
meeting of the Society for Neuroscience in New Orleans.

New Addiction Medication

A new chemical candidate for treating cocaine addiction, called RTI113, is
similar in structure to cocaine. It is one of a new class of compounds
called phenyltropanes, which alter the same neuronal systems targeted by
cocaine and related drugs, but are thought to have a lower abuse liability
and minimal side effects and toxicity. Once in the brain, RTI113 selects
and binds successfully to the same dopamine transporters that cocaine
targets. It is potent, yet it enters the brain more slowly than cocaine.
Most addicting drugs have a rapid entry to the brain, accounting for the
"rush" felt by users. RTI113 is also longlasting, which facilitates an
easy dosing schedule in a treatment setting.

In monkeys, RTI113 substitutes completely for cocaine, resulting in a
reduction in the monkeys' cocaine selfadministration, which is the best
model of drugseeking and drugtaking behavior in humans.

In people, the medication would be taken orally to relieve craving for
cocaine, and thus help manage the urge for "outofcontrol," illegal, and
destructive drugseeking behaviors. "This type of therapy is a critical
first step in getting an addict off cocaine and into a treatment and social
support program," says Mike Kuhar, Ph.D., Chief of the Neuroscience
Division at Yerkes. "It is not a cure, but a major step in reducing drug
use and its enormous cost to society, in terms of physical and mental
health, crime, and safety." The goal, he says, is to develop a medication
that can be controlled and dispensed by a treatment center physician, and
will act as a safe stepping stone in the process of withdrawal. It would
provide the addict and the treatmentcenter staff the control needed to set
in place a detoxification program. Many addicts leave treatment because of
the persistent, demoralizing urge to find drugs. "A medication to break
this cycle is essential," says Kuhar.

Dr. Kuhar and his colleagues, particularly Dr. Ivy Carroll, a medicinal
chemist, began synthesizing phenyltropanes 10 years ago. From nearly 500
compounds, they have narrowed the field to about 25 candidates for further
testing. Because compounds cannot be tested in humans unless they are
proven likely to be safe and effective, rat or monkey models are used. In
the selfadministration model, an animal is given the opportunity to obtain
an injection of a drug by pressing a lever. If the animal likes the drug,
it will press the lever again and again. However, the animals are permitted
access to the drug only in very short intervals to avoid toxic effects and
are closely monitored.

Cocaine Studies Help Explain How Brain Regulates Hunger

Studies on the effects of cocaine in the brain led to the discovery by
Yerkes neuroscientists that feeding behavior and perhaps satiety is
controlled at least in part by a novel group of naturally occurring brain
peptides. Specifically, the peptides inhibit food intake in animals, and
thus may be useful in developing medications to help treat obesity, bulimia
and anorexia nervosaserious, yet common illnesses that can be
lifethreatening and are often at the root of various other health
problems, such as diabetes and cardiovascular disease.

The brain peptides are made from an mRNA transcript named CART, for Cocaine
and Amphetamine Regulated Transcript. CART was found by examining changes
in the brain following cocaine or amphetamine administration.
Neuroscientist Pastor Couceyro was one of the first to notice that CART
mRNA increased with cocaine administration. Because they knew that
behaviorally, cocaine use reduces food intake, the Yerkes team tested CART
to see if it might be the agent responsible for the loss of appetite.

"When we injected the CART peptide into the brains of rats, their food
intake was significantly inhibitedby as much as 30 percent," explains
Dr. Phil Lambert, who handled the behavioral aspect of the work. Similarly,
when they blocked the brain's naturallyoccurring CART peptides (by
injecting antibodies which bind the to the peptides) the rats' feeding
increased. "This antibody data is what makes us think CART is responsible
in part for making you feel satedwhether it's after eating, or after
cocaine use," explains Dr. Lambert.

When Yerkes scientists examined the location of CART peptides in the brain,
they were in fact present in high levels in regions known to be involved in
control of food intake. The next steps are to identify the precise
structure of the CART peptides and to further explore their role in
managing an animal's body weight. "We are very excited about this new
potential neurotransmitter link to feeding," says Dr. Couceyro. "We can
keep one eye on the mechanisms of cocaine addiction and one eye on basic
physiology governing hunger." This could prove especially important to the
59 percent of Americans who, according to 1995 figures by the Institute of
Medicine, are clinically obese.

Yerkes scientists caution that CART is only part of the feeding story. They
believe that there are many chemicals in the brain regulating food intake
and that if one is knocked out of commission, the brain will eventually
learn to compensate. Eating is too important an activity to have just one
neurotransmitter responsible. The Yerkes team is looking for a final common
pathway for the foodrelated chemicals and their receptors.

"Examining food intake in humans is difficult because people don't
necessarily eat just when they're hungry," explains Dr. Lambert. They are
more dependent on social cues, timetables and taste than are animals.
Generally, animals don't expend their energy unless they need to, and eat
only when hungry. However, if fed certain sweet mixtures, taste does tend
to take over.

The Yerkes Primate Center is part of the Woodruff Health Sciences Center of
Emory University, and is the oldest scientific institute in the world
dedicated to primate research. Its programs cover a wide range of
biomedical and behavioral sciences.

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