By David N. Leff

With alternative medicine attracting increased acceptance, how about a compound that claims to stimulate appetite, facilitate learning and memory, modulate locomotion, inhibit seizures, produce hypothermia, moderate sexual behavior and reduce anxiety?

This is no miracle drug extracted in ancient times from herbs. Rather, it's a substance that every mammal makes inside its own head. In the late 1990s, scientists have noted the effects listed above in legions of laboratory rats and mice.

The molecule's name is neuropeptide Y (NPY). It's a potent and widespread neurotransmitter in the brain, spinal cord and outlying neurons. NPY was discovered in 1882.

Endorphin is a neuropeptide (NP). When discovered in the mid-1970s, it was hailed as "the brain's own opiate," because it bound morphine. Endorphine comprises five amino acids; NPY, 36.

"NP and NPY are separate, unique peptides," observed research psychologist Todd Thiele. "They're made from different precursors. I guess it's possible," he added, "that NPY and endorphin are working together in some way in the brain." Thiele is a research scientist at the University of Washington, in Seattle.

"There's a lot of evidence," he told BioWorld Today, "to indicate that NPY does a variety of things, depending on what part of the brain you're talking about. In the hypothalamus, NPY seems to be a strong inducer of eating, suggesting that in that region it regulates food intake.

"NPY given into another brain region," he said, "seems to produce anxiolytic effects. In other words, if you have a stressed rat or mouse and you put NPY into the amygdala, the animals become calm. So NPY seems to have anxiety-reducing qualities."

Thiele also cited very recent evidence that NPY may be useful for treating and terminating seizures. "So it seems," he observed, "that NPY has a variety of neuroprotective functions. Which one might be related to its effects on alcoholism is an interesting question that we need to pursue."

Thiele is lead author of a paper in the current Nature, dated Nov. 26, 1998, titled "Ethanol consumption and resistance are inversely related to neuropeptide Y levels."

"The overall reason that we ran the study," he said, "was to directly assess the possibility that NPY might be involved with regulating ethanol intake, at least in mice. A group of researchers at the Indiana School of Medicine had bred two lines of rats; one drinks a lot of alcohol, the other doesn't drink much at all.

"They had evidence indicating that low levels of NPY in the brain of these alcohol-preferring rats might be related to their high alcohol preference," Thiele said. "That is, these genetically bred rodents have normally low levels of NPY in the brain, and they like alcohol. That's correlational.

"Our objective was to test directly, by manipulating the NPY levels in mice, whether that neurotransmitter is related to alcohol intake."

To undertake this project, Thiele and his co-authors enlisted a strain of knockout mice in which the NPY gene was disrupted, so they did not produce any detectable levels of the molecule.

They found that those NPY-lacking animals showed significantly higher levels of alcohol intake compared to normal mice. "They were also less affected by the sedative, or sleep-inducing, effects of ethanol," Thiele noted, "so when we administered alcohol to them, they woke up much sooner than normal mice. That is, they drank more alcohol, but were less affected by its intoxicating effects."

The team also ran an opposite study in transgenic mice genetically altered to overexpress NPY in their brains. These high-NPY animals drank less alcohol relative to normal mice, but were more affected by the sedative effects of the ethanol. "This is the first demonstration," Thiele said, "that changing the amount of NPY present in the brains of rodents alters their level of alcohol consumption."

Extrapolating this finding to alcoholism in people is another matter.

"Of course, we humans produce NPY in our brains," Thiele said. "And there's been a lot of theorizing that low or abnormal NPY levels in humans might account for certain conditions, such as depression, anxiety, perhaps drug-addiction disorders."

He "strongly suspects" that pharmaceutical companies will take note of his Nature paper, "because I know there are pharmaceutical companies that are looking into the possibility of making NPY compounds to treat other symptoms, such as obesity." He explained: "There seems to be a hypothalamus-mediated relation between NPY and food intake. So it wouldn't be too hard to imagine that companies might become interested in looking for NPY compounds that could be useful in treating drug disorders or alcoholism.

Before Prospective Applications — Receptors

"For any neurotransmitter system there are a variety of receptors," Thiele noted. "And our hope would be to find the critical receptor that NPY acts on to influence feeding, for example. Hopefully, we'll find that there are different, unique receptors that are important for NPY to have an effect not only on alcohol intake, but anxiety, obesity and so on." He added, "If we can discover these specific and unique receptors that regulate each one of these systems independently, then it becomes a much more practical proposition to try to find compounds that are able to treat each of these different disorders without interfering with each other."

"This study [in Nature] is important for two reasons," commented Enoch Gordis, director of the National Institute on Alcohol Abuse and Alcoholism. "It indicates that peptides related to appetite and anxiety are significant areas for study in alcohol research, and that drugs designed to interact with components of the neuropeptide Y signaling system may someday be useful in helping individuals control their alcohol consumption." *