May 6, 1998 ATLANTA - Neuroscientists at the Yerkes Primate Research Center of Emory University have discovered in the brain a novel neurotransmitter that helps control food intake and seems to be partially responsible for the feeling of satiety. The finding may eventually be used to develop medications for obesity, a life-threatening, yet common condition that often lies at the root of other serious illnesses such as diabetes and cardiovascular disease. The study will be reported in the journal Synapse (vol 29, No. 4), available in May on the Synapse website. The neurotransmitter is called CART peptide, for Cocaine and Amphetamine Regulated Transcript, and its role in feeding was found during studies on the effects of cocaine on the brain. Yerkes neuroscientist Pastor Couceyro was one of the first to notice in rodents that CART mRNA increased in a specific area of the brain when cocaine was administered..
"We tested the CART peptide to see if it could be an agent responsible for loss of appetite for two reasons," says Mike Kuhar, Ph.D., Chief of Neuroscience Division at Yerkes. "First, CART is associated with cocaine and cocaine reduces food intake. Also, CART peptides are found in regions of the brain that control food intake."
When the Yerkes research team injected the CART peptide into the brains of normal rats, their food intake was significantly inhibited--by as much as 30 percent, according to Dr. Phil Lambert, who completed the behavioral aspect of the work. In normal rats, CART was present in high levels in the hypothalamus, "meaning that CART is apparently involved in a variety of physiologic processes, not just in cocaine addiction," says Dr. Lambert.
Next Lambert tried the flip side of the experiment-- blocking the brain's naturally-occurring CART peptides by injecting antibodies (which bind to the CART peptides and render them non-functional). Without CART peptides to put the brakes on appetite, the rats' feeding increased. "This antibody data is what makes us think CART is responsible, at least partially, for making you feel sated -- whether it's after eating, or perhaps after cocaine use," explains Dr. Lambert.
To further support the evidence that CART plays a major role in influencing appetite, Dr. Lambert found that CART interacts anatomically and functionally with a substance called neuropeptide Y (NPY), a neurotransmitter known for years as a strong hunger stimulant. "We may be completing more of the food intake picture," says Dr. Kuhar. "Although NPY has been well characterized as a catalyst for hunger, agents that mediate satiety are not fully identified. This seems to be a part of the puzzle."
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, especially long-term. This could prove especially important to the 59 percent of Americans who, according to the Institute of Medicine (1995), are clinically obese. It could also help those suffering from bulimia and anorexia nervosa. The fact that CART appears to be a neurotransmitter is significant, because neurotransmitters are by definition related to the control of normal physiological processes and are easily modulated for treatment purposes.
Yerkes scientists caution that CART is only part of the feeding story. There are many chemicals in the brain regulating food intake and if one is knocked out of commission, the brain will eventually learn to compensate. "Eating is too important an activity for survival to have just one pathway responsible," says Dr. Lambert. The Yerkes team is looking for a final common pathway traveled by all the feeding-related peptides and their receptors. Using rodents for such studies is necessary for these early studies because "humans don't necessarily eat just when they're hungry," says Dr. Lambert. "They are more dependent than most animals on social cues and timetables."
The CART studies show potential for more than just obesity studies. Dr. Kuhar and his colleagues believe the family of CART peptides can still reveal much about the mechanisms of addiction, and possibly even stress-related disorders, as the peptides are also localized in areas of the brain involved in stress.
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