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UND study probes inherited component of drug addiction

GRAND FORKS, N.D.--A five-year study underway at the University of North Dakota is attempting to figure out how addictive tendencies could pass from one generation to the next.

GRAND FORKS, N.D.-A five-year study underway at the University of North Dakota is attempting to figure out how addictive tendencies could pass from one generation to the next.

To do that, researchers are employing the help of a $1.5 million grant from the National Institute on Drug Abuse, along with a set of microscopic research assistants-tiny worms known as nematodes. UND associate professor Lucia Carvelli, the leader of the study, said the goal of her research is to identify the pathways by which amphetamine use can have deep long-term effects for both users and their progeny.

Carvelli said researchers have suspected a genetic component to addiction for more than 50 years, but have yet to find any kind of "addiction genes" that adequately explain how addiction might be an inheritable trait.

"It had to be something else," she said. "So what about the mechanism that controls gene expression?"

Drug addiction produces behavioral effects that are readily observed; users react a certain way after ingesting a drug and tend to follow patterns of action to re-create pleasurable feelings brought on by their substance of choice.

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The true effects of addiction can go even deeper. Carvelli said use of stimulants and other drugs can leave behind observable molecular changes in brain cells, also called neurons, that affect the rate at which dopamine-a kind of chemical produced by neurons and associated with feelings of pleasure-is reabsorbed after surging due to drug use.

What's more, while addiction might not be written directly into the genes of a drug user's DNA proteins, it does seem to have an impact on a closely related set of information. These additional bundles of proteins which help translate genetic code into actual characteristics are studied under the field of epigenetics.

These behavioral, molecular and epigenetic changes caused by addiction all function as adaptations to the condition. If passed down through generations, these alterations could place the offspring of an addicted individual at a greater risk of developing an addiction themselves.

As her study progresses, Carvelli said researchers will probe how amphetamines and other drugs can lead to such changes. The long-term goal of the study will examine how alterations in the epigenetics of neurons might be replicated in sperm and egg cells-the cells responsible for reproduction.

Useful test subject

For all of these things, the nematode has proven to be a useful test subject.

Carvelli said the worms' brains are very simple in comparison to those of human beings. A nematode has a total of about 300 neurons. Our brains are made up of billions of neurons.

"From an evolutionary point of view, it's pretty far away from a human being," Carvelli said of the nematode. "But they have highly similar (dopamine-processing) neurons. They produce the same proteins, the same neurotransmitters, they work the same way as they do in mammals or human beings. We can focus specifically on that."

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Nematodes usually live simple, drug-free lives in watery habitats. Carvelli said they busy themselves with the act of multiplying and are essentially "eating and reproducing machines."

In the lab, that equation is slightly altered. Carvelli said one of the first experiments the researchers do involves putting nematodes in a container with just water-a set of worms known as the control group-or with water spiked with cocaine or amphetamines.

The worms don't respond to the drugs the same way people usually do-Carvelli said they cease their usual frantic pace of swimming and relax in a "peaceful" manner after being given stimulants-but they do exhibit certain changes that mirror the ways addiction affects human beings.

Nematodes exposed to drugs while in their embryonic stage are more sensitive to a second exposure as adults than those whose first exposure came later in life. Researchers also have observed changes in the molecular structures involved in the dopamine re-uptake process in drug-exposed nematodes, changes not seen in the undrugged worms.

Further, the epigenetics of the exposed nematodes show alterations from those found in the worms of the control group.

Carvelli said researchers know how drugs can enter cells but still don't know how they manage to enter the cells' nucleus, the central cellular warehouse of genetic information.

From there, it's further unknown how drugs manage to rewrite some of that information. Working down those lines of inquiry is a major part of realizing the larger goal of Carvelli's research.

"If one thing happens in one cell, then that cell can memorize that effect and it can stay there until the animal dies," she said, "but that thing, that mechanism, it's not just staying in the cells-it's being transmitted."

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