Feb. 15, 1999
Volume 51, No. 20
Kuhar's cocaine research uncovers weight loss benefit
In the mid-'80s America's poorer urban neighborhoods slowly began unraveling as a new and more deadly drug hit the streets: crack. An even more potent form of powdered cocaine, crack was found to be more addicting, and the street life that surrounded its use led to a whole new type of addict, one even more difficult to treat. The federal government took notice and a renewed emphasis was placed on understanding this drug and on finding a treatment.
In 1995 researchers at the Vollum Institute in Oregon noticed that cocaine-drugged rats produced an increased level of a messenger RNA (mRNA) in the brain. In cells, DNA is copied into mRNA form, and RNA is then copied into a protein or peptide form--the final product of the DNA message. Knowing this, researchers wondered if the mRNA they had discovered might be the cause of cocaine's effects. They called their finding CART, for cocaine and amphetamine regulated transcript.
"It was postulated that the product of CART, the peptide, would be involved in the action of cocaine amphetamine. If the precursor (mRNA) goes up, there must be demand for the product (peptide)," said Yerkes researcher and Georgia Research Alliance Eminent Scholar Michael Kuhar.
Kuhar has been studying cocaine for years, trying to find a medication to counter its ill effects. He became interested in CART and began his research by asking three questions: Is CART made in the brain? Are these parts of the brain the same parts involved in addiction? Does CART peptide affect the body?
To begin his research Kuhar collaborated with Neurocrine Corp. to derive CART peptide antibodies that would bind to the peptide and allow him to see where and when the protein was being produced. The antibodies showed that cocaine-injected rats produced high CART levels in brain areas involved in drug addiction.
Next he injected rats with the CART peptide. Like the rats given cocaine, these animals showed increased activity and a lack of hunger. In short, the answer to all three of his questions was yes. But the study's results had even more interesting applications. "Drugs that affect CART may be useful in treating eating disorders," said Kuhar.
Kuhar's lab found CART in the hypothalamus, the area of the brain that controls a number of physiological processes, including food intake. And results from the feeding study found rats consuming about 30 percent less food than rats not given the CART peptide.
"Because of the serious problem of obesity in some parts of the world, there is a huge market for anti-obesity drugs," Kuhar said. Because of this many companies have gotten excited about the CART peptide. One Danish company has begun conducting trials on CART, and several large American drug companies are starting similar ventures.
These studies may also lead to therapy for anorexia as well, since turning off CART might increase hunger.
Meanwhile, Kuhar has begun to focus on locating the receptor for the CART peptide and in discovering CART agonists and antagonists--agonists mimic the effects of a substance while antagonists block them. Unlike the CART peptide, these therapeutic drugs will be taken orally. CART cannot be taken orally because, like most proteins, it is broken down in the digestive track.
Kuhar said he remains uncertain as to what the studies on CART will reveal next. But he is excited about the possibilities, adding that CART may even be involved in stress-related disorders as it also is found in areas of the brain involved in stress.