Modified mice lend clue to how nicotine works

French scientists have created a mouse that has no interest in nicotine and then reintroduced a brain receptor that rekindles the animal's craving for the toxic substance.

The achievement narrows the search for the chemical triggers in the human brain that are responsible for smoking addiction, and points to what could be the first specific target for treatment.

"This is a very important finding," said Julie Kauer, an associate professor of molecular pharmacology, physiology and biotechnology at Brown University in Rhode Island.

Kauer wrote an accompanying editorial in Nature, where the nicotine study appears this week: "We all want to know how nicotine works. This brings us close to the target."

Jean-Pierre Changeux of the CNRS/Institut Pasteur in Paris and his colleagues have spent a decade unraveling the mysteries of genes and their interactions with behavior. Scientists have known for decades that the brain recognizes nicotine through a complex set of chemicals orchestrated by nicotinic acetylcholine receptors, found all over the brain.

But there are many subtypes of this receptor, active in specific parts of the brain, and that has made it difficult to figure out what the brain actually does in response to nicotine — a stimulant that has powerful and deadly addictive properties.

Changeux's team bred mice that lack a specific sub-unit of the nicotinic receptor called beta-2. This subunit is normally found in abundance in a region of the brain called the ventral tegmental area, or VTA. When bred without these receptors, mice have no interest in nicotine.

In the latest study, the researchers reintroduced the receptor into the VTA and watched as the animals began seeking and consuming an unlimited supply of nicotine. The scientists also discovered that even without exposure to nicotine, the animals with beta-2 receptors were far more inquisitive than their littermates. This suggests, Kauer said, that the beta-2 receptor has a role in discovery and learning.

It also was proof that the two properties of nicotine — its stimulating effects and its powerful addicting nature — are tied to the same brain region. The same chemical systems exist in mice and humans.

"It's exciting when you can figure out that a part of the brain controls a specific behavior," Kauer said.

The VTA is loaded with dopamine cells related to reward and addiction.

"This is the ultimate test," added Stephen Dewey, an addiction expert at Brookhaven National Laboratory in Upton. "Knock out the receptors, lose the behavior. Put the receptors back, and watch the behavior return. It's powerful."