Scientists find link for smoking, schizophrenia

Schizophrenia Update, January 2004

Source:Canadian Press

TORONTO - A team of Toronto researchers has made a startling discovery about why people with schizophrenia are so much more likely than other people to be smokers.

Medications that block dopamine - commonly used by people with this debilitating condition - make smoking a more rewarding experience, they reported Friday in the journal Molecular Psychiatry.

The findings, which challenge long-held views about the role of dopamine in nicotine addiction, may provide science with clues on how to help schizophrenics and others give up cigarettes and kick other habit-forming drugs.

"It's a first step in identifying systems in the brain that can mediate vulnerability to addiction," said lead author Steve Laviolette, who is currently doing post-doctoral research at the University of Pittsburgh.

He admitted, however, that the findings are likely to spark controversy.

"It's basically overturning 30 years of previous research. So you might come across people who are hostile to - if not shocked by - the results."

Yavin Shaham, an addiction researcher at the U.S. National Institute on Drug Abuse in Baltimore, Md., agreed that the findings defy some of the dogma around nicotine addiction. But he said the science is sound and the findings will spark debate in the addiction research community.

"I think that it's very interesting research that points in new directions to understanding nicotine reward," said Shaham, who was not involved in the research.

"It's not necessarily the way we thought about it in the past. And it's certainly relevant for the understanding of why schizophrenics are smoking so much."

Laviolette wrote the paper with co-author Derek van der Kooy while working on his doctorate in neuropharmacology at the University of Toronto. The pair was trying to identify areas in the brain that are involved in nicotine addiction.

"The schizophrenic angle came up almost accidentally, really," Laviolette said from Pittsburgh.

The work, done on rats, involved injecting nicotine or a placebo - in this case saline - directly into a portion of the brain known as the ventral tegmental area, or VTA. The VTA is thought to be the pleasure centre of the brain and is known to be involved in nicotine, alcohol and drug addiction.

To the team's surprise, they discovered the VTA also is involved in aversion. Low doses of nicotine administered to that area of the brain actually induced a negative reaction from the rats. It was only when the dosage crossed a certain threshold that the animals began to perceive it as pleasurable and to seek it out.

"That was surprising, that a single brain area was responsible for both the aversive and the rewarding effects," Laviolette admitted.

More surprising still was what happened when they gave the rats drugs that blocked the dopamine receptors in the VTA.

For decades, research has shown that dopamine, a neurotransmitter, is responsible for the rewarding effects of nicotine. But researchers could never explain why people with schizophrenia on dopamine-blocking drugs tend to smoke like chimneys.

It didn't seem to make sense: if dopamine allowed the brain to enjoy smoking and dopamine was blocked, smoking should no longer be a pleasurable experience.

"And what was the surprising thing was the rewarding effects were not blocked at all," Laviolette said of the rat experiments.

In fact, the contrary was true, he said. Blocking dopamine blocked the adverse effects of nicotine, but ramped up the rewarding sensations induced by the drug. Dramatically.

The findings suggest that schizophrenia medications that block dopamine are fixing one problem but causing another, he said.

"What's really happening is that you're blocking dopamine in the schizophrenics, you're increasing nicotine's rewarding effects. And that's why you see 95 per cent of schizophrenics are heavily addicted to nicotine."

Further, the same effect is probably happening with alcohol and possibly other drugs, Laviolette said.

"It's a two-edged sword. The drug is removing the psychosis but at the same time making them addicted to these extremely dangerous drugs."

Not all medications used to treat schizophrenia work by blocking dopamine, however. The newer generation of medications, known as atypical anti-psychotic drugs, work by a different mechanism.

Laviolette said the research suggests that the reactions to a drug induced in the VTA fall on a spectrum from aversion to pleasure. Whether one finds a cigarette satisfying or disgusting may depend on one's baseline dopamine levels, he said.

"So depending on how those two systems in the VTA are balanced in terms of dopamine, that could be a clue as to which person may be more vulnerable to become addicted to certain drugs."




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