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Therapeutic Drug Blocks Nicotine's Effects on Brain ChemistryStudy in rats may lead to treatment for nicotine addiction in humans

UPTON, NY -- Nicotine is widely believed to trigger dependence by elevating certain brain chemicals associated with pleasure and reward. Now, a study in rats at the U.S. Department of Energy's Brookhaven National Laboratory shows that topiramate -- a new anticonvulsant drug sold under the brand name Topomax(r), currently used for the treatment of epilepsy -- can block some of the nicotine-triggered changes in brain chemistry, and may have potential for the treatment of nicotine addiction in humans.

"This treatment strategy uses a drug that simultaneously targets two different neurotransmitter pathways, thereby reducing the neurochemical activity believed to underlie nicotine addiction," said Wynne Schiffer, lead author of the study. The findings appear in the December 1, 2001, issue of the journal Synapse.

Brookhaven scientists have been studying the neurochemistry of drug addiction for nearly two decades, and have used information gathered from these studies to investigate potential pharmacologic treatments for drug abuse. Previous studies focused on agents that block drug-induced increases in brain dopamine, a neurotransmitter associated with pleasure and reward.

"But new theories about nicotine dependence suggest that dopamine isn't the only system involved," said Brookhaven neuroanatomist Stephen Dewey, a coauthor on the study. For example, nicotine stimulates specific excitatory systems in the brain, and these systems excite not only dopamine but a host of other brain chemicals, such as norepinephrine and serotonin.

Schiffer, a Stony Brook University Department of Neurobiology graduate student who works with Dewey, suggested studying topiramate because it is believed to control the brain's reward pathways by two distinct mechanisms: 1) by reducing excitatory input to the dopamine system, and 2) by raising the activity of GABA, a brain chemical that inhibits dopamine.

In the current study, scientists injected one group of rats with topiramate while another group received control injections of saline. The scientists then gave both groups an acute dose of nicotine and measured dopamine, norepinephrine, and serotonin levels in their brains. Animals given topiramate but no nicotine were also studied to see if topiramate alone had any effect on the neurotransmitters. The scientists also tested the effect of topiramate on dopamine in animals that had been pretreated with nicotine for 14 days prior to the experiment, to serve as a model for humans addicted to the drug.

As expected, animals that received saline and then nicotine showed significant increases in all three brain chemicals. Rats that had been previously "addicted" to nicotine showed even greater elevations in brain dopamine than those that received just the acute dose -- similar to what you'd expect to see in a smoker who has a cigarette after a period of not smoking.

Pretreatment with topiramate, however, completely blocked nicotine-triggered increases in norepinephrine and dopamine -- and even modulated the dopamine response in the "addicted" animals. "Since the brain's dopamine and norepinephrine systems are closely linked, the ability of topiramate to reduce increases in both neurotransmitters suggests that this drug has potential for treating nicotine abuse," Schiffer said.

Topiramate did not significantly modulate the effect of nicotine on serotonin, however. In fact, serotonin was the only neurotransmitter affected by topiramate alone, showing a slight increase.

Human studies conducted elsewhere suggest that specific drugs that increase serotonin appear to diminish the incidence of smoking. From this, the researchers propose that the ability of topiramate to increase serotonin activity, while at the same time controlling dopamine and norepinephrine, might contribute to its promise as a treatment for nicotine addiction.

This work was funded by the U.S. Department of Energy, which supports basic research in a variety of scientific fields; the National Institute of Mental Health; and the National Institute on Drug Abuse.

The U.S. Department of Energy's Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies. Brookhaven also builds and operates major facilities available to university, industrial, and government scientists. The Laboratory is managed by Brookhaven Science Associates, a limited liability company founded by Stony Brook University and Battelle, a nonprofit applied science and technology organization.

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Note to local editors: Wynne Schiffer lives in Sound Beach, New York; Stephen Dewey lives in Manorville, New York.