Science Editor

The consequences of addiction, in both cold hard medical costs and sheer human misery, dwarf most other disorders. And among addictions, because it is legal, nicotine is one of the biggest ones. Even in the U.S., where smoking has been declining for decades, tens of millions of people still light up regularly, and tobacco remains the leading cause of preventable death.

This week, scientists reported a new mechanism for nicotine addiction, as well as a new brain pathway involved. The work, which in the estimation of senior author Paul Kenny could lead to "a whole different paradigm for treating addiction," was published in the Jan. 30, 2011, online edition of Nature. Kenny is associate professor of molecular therapy at the Scripps Research Institute Florida.

It may be surprising given tobacco's medical importance, but "nobody really knows precisely which nicotinic receptors regulate the effects of nicotine," Kenny told BioWorld Today. There is clearly a strong genetic component to addiction; but there are also a plethora of subunits that can assemble in many different ways, and the exact details of which ones are responsible for addiction remain to be worked out.

In their studies, Kenny's team focused on the effects of one subunit, the alpha-5 subunit.

The work was prompted by genomewide association findings that variations in the alpha 5 subunit influenced their owners' risks for both smoking and lung cancer. And puzzlingly, those receptors seemed to have a paradoxical effect. "Polymorphisms that increased vulnerability to addiction appeared to decrease receptor function," Kenny said.

It might seem obvious that the more sensitive someone is to nicotine, the more likely he is to become addicted. But the new work also shows that the alpha-5 receptor subtype works as a shut-off valve once a certain brain level of nicotine has been reached, and so the opposite is true.

Kenny and his team began exploring the effects of nicotine on alpha 5 receptors by allowing both alpha 5 knockouts and normal animals to dose themselves with nicotine. When mice are given the chance to get high off of nicotine (or any other drug, for that matter), their response will usually depend on the dose: intermediate doses will be eagerly accepted, whereas animals will not self-administer as much of a higher dose.

Alpha 5 knockouts, too, will sooner or later become less enthusiastic about higher-dose drugs. But the doses it takes to get them to the point of diminishing returns are much higher than those of control animals.

Alpha 5 receptors show an unusual distribution in the brain. They are "very heavily enriched," Kenny said, in an area of the midbrain known as the habenula, and in the interpeduncular tract to which it projects. This area of the brain is involved with avoiding poisons, but few studies had previously linked the pathway to drug-taking behavior.

Kenny and his team found that knocking down alpha 5 subunits specifically in this brain area also led rats to give themselves higher levels of nicotine.

In their paper, Kenny and his team suggested why. When nicotine acts on receptors in the habenula and interpeduncular tract that contain the alpha 5 subunit, it actually triggers an inhibitory behavioral response. And when the receptors in the tract are not working, it essentially removes the brakes on nicotine consumption, ultimately leading to exposure to more nicotine, and its associated health problems.

First author Christine Fowler explained in a prepared statement, "The habenula appears to be activated by nicotine when consumption of the drug has reached an adverse level. But if the pathway isn't functioning properly, you simply take more."

The work, Kenny added, leads to "a whole different paradigm for treating addiction. . . . If you could make drugs that increase receptor function, our work suggests that those could be helpful in treating nicotine addiction." His team is now in the early stages of identifying such activators.

Kenny and his colleagues also contend that alpha 5 receptors may be involved in other drug additions, such as alcohol, and so could possibly be used to treat addiction more generally. While nicotine activates the receptor directly, alcohol would do so indirectly, he explained: "Alcohol may influence acetylcholine transmission in the habenula-interpeduncular pathway. . . [and] acetylcholine acts at nicotinic receptors containing alpha 5 subunits."