Oct. 27, 1997 NEW ORLEANS--Researchers 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 RTI-113, 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, RTI-113 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. RTI-113 is also long-lasting, which facilitates an easy dosing schedule in a treatment setting.
In monkeys, RTI-113 substitutes completely for cocaine, resulting in a reduction in the monkeys' cocaine self-administration, which is the best model of drug-seeking and drug-taking behavior in humans.
In people, the medication would be taken orally to relieve craving for cocaine, and thus help manage the urge for "out-of-control," illegal, and destructive drug-seeking 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 treatment-center 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 self-administration 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 nervosa----serious, yet common illnesses that can be life-threatening 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 inhibited----by as much as 30 percent," explains Dr. Phil Lambert, who handled the behavioral aspect of the work. Similarly, when they blocked the brain's naturally-occurring 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 sated-----whether 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 food-related 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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