Smoking's reward: nicotine triggers opiate-pleasure response.

For any smoker trying to quit, tobacco's addictive nature is abundantly clear. However, the mechanism behind the leaf's habit-forming properties has been hazy. Now, a study of mouse brains suggests that nicotine, the chemical considered the foundation of tobacco cravings, works via the same pathways that give morphine and other opiates their addictively rewarding qualities.

In previous studies, Julie Blendy of the University of Pennsylvania in Philadelphia and her colleagues used genetically modified mice that were unable to produce a brain protein called cyclic AMP-response element binding protein (CREB). Unlike normal mice, the CREB-deficient rodents seemed to receive no reward from morphine or nicotine and formed no attachment to these highly addictive drugs.

Although the researchers weren't sure how CREB works in the brain, "we thought that maybe this protein is a common link" between the mechanisms of tobacco and morphine addiction, says Blendy.

To investigate their hunch, Blendy and her colleagues focused on normal mice. The team injected these animals with enough nicotine to provide a rewarding sensation seemingly similar to a person's experience of smoking a cigarette. After dissecting the mice's brains, the researchers found that CREB had switched to an activated form in a brain region called the ventral tegmental area. Previous studies had implicated this region in habit formation for other addictive drugs, such as cocaine and phencyclidine (PCP).

Next, the researchers found that the activated CREB was binding to regions of DNA that increase production of mu-opioid receptors on nerve cells. These receptors respond both to opiate drugs, such as morphine, and to the body's morphinelike chemicals.

Thus, suggests Blendy, the rewarding effects of the body's native opioids can be enhanced by nicotine in a cigarette.

Blendy's team added evidence to this hypothesis by studying CREB's activity in an environment that triggered cravings in nicotine-addicted mice. The researchers tested normal mice, mice treated with a drug that blocks mu-opioid receptors, and CREB-deficient mice.

They placed each mouse, one at a time, in a box having two chambers. In one of the chambers, some mice received nicotine injections every other day. Other mice received saline injections in the same chamber on that schedule. All the mice received saline injections in the opposite chamber on the other days.

After 8 days, the researchers found that normal mice injected with nicotine preferred to stay in the chamber where they had received the drug. Brains from those mice contained activated CREB, even though the animals hadn't received additional nicotine. In contrast, CREB-deficient mice and those treated with the receptor-blocking drug showed no preference for either side of the box.

Blendy's team reports its findings in the June 16 Neuron.

Marina Picciotto, a professor of psychiatry at Yale University, says that the findings suggest that nicotine's action ultimately relies on mu-opioid receptors, much as the actions of many other addictive drugs do. "There are common circuits involved in mediating the effects of these drugs of abuse," she says.