21 August 2002 11:15 EST

by Tabitha M. Powledge, BioMedNet News

A common and inexpensive drug, in everyday use for hundreds of years by hundreds of millions of people, shows signs of being therapeutic for a long list of ills - attention-deficit hyperactivity disorder, Alzheimer's disease, pain, depression and anxiety, and even obesity, among others. Yet research interest in this potential cure-all has been slow to develop.

One reason is that the drug in its current forms offers drug companies no possibility of substantial profit. A second reason, perhaps more important, is that it is reviled as the world's most addictive drug: nicotine.

Nevertheless, nicotine may at last be transformed from sow's ear to silk purse, building on foundations laid in the past 20 years by a few researchers fascinated by the drug's properties, both good and evil. There is now strong evidence, for example, that nicotine affects appetite regulation and attentional focusing and distractibility, says Neil E. Grunberg, long-time nicotine researcher at the Uniformed Services University of the Health Sciences in Bethesda, Maryland.

"Another one I think looks really good based on data I've seen - but I don't know if anyone is trying to develop it - is nicotine as an analgesic, perhaps on its own or as an adjunct," Grunberg said. Because of nicotine's addiction potential, the Food and Drug Administration would probably balk at permitting the addition of nicotine to aspirin. But he speculates that the agency might go along with adding it to morphine in a controlled hospital situation: "It might potentiate the analgesic action and decrease the amount of these other powerful drugs."

Kenneth Kellar of Georgetown University in Washington, DC, reported two decades ago that nicotine administration increases the number of nicotinic receptors in rat brains. He points out that in vitro and animal studies have shown that nicotine can protect neurons against damage and death. "It probably interferes with apoptosis, but no one knows for sure," Kellar said. In any case, the potential applications ­ which include stroke and spinal-cord injury - are many.

Along with two other long-time nicotine researchers, Paul Newhouse of the University of Vermont College of Medicine, and Edward D. Levin of Duke University, Kellar is planning to study the effects of nicotine on older people with minimal cognitive impairment (MCI), a mild condition that some view as a precursor to Alzheimer's disease. "We're not going to cure or reverse Alzheimer's, " Kellar said, "but if we can slow things down for a year, we will have done a great service."

Kellar says the MCI study will employ nicotine skin patches, which are widely sold without prescription as temporary aids to quitting smoking. But nicotine in a patch is a blunt instrument. The drug affects a huge array of neurotransmitter systems, with the result, for example, that it increases heart rate and blood pressure. So researchers have been looking for nicotine-like drugs that will affect the various subtypes of nicotinic receptors selectively.

This is no simple search. "It's taking a lot of work to try to determine which neurotransmitter interactions and which nicotine receptor subtypes are involved with which functional effects," Levin said. Still, "if we can separate out the effects of nicotine stimulation on increasing blood pressure or heart rate or addiction liability from those that improve cognitive performance or reduce weight or anxiety or pain, then we can help with the drug development effort as well as get some more basic information about how the brain works." Several pharmaceutical companies are reportedly working on synthetic nicotine analogs that target a single receptor (and thus are patentable).

Newhouse thinks the work is proving difficult because the receptors are ion channels. "This system seems to be a little harder and more tricky to push around than, say, the G protein-linked systems that many of our psychotropic drugs work on," he said.

The hottest preclinical research areas for possible nicotine-based treatment, according to Grunberg, are schizophrenia, anxiety, and depression. Some 90% of schizophrenics smoke, leading to speculation that they might be trying to self-medicate with nicotine. But in two years of work with an animal model of schizophrenia, researchers in his lab have failed to show that nicotine alleviates schizophrenic-like symptoms. They continue to believe in the drug's therapeutic potential, however. "It may not be affecting the thought disorder," Grunberg said, "but rather the mood-altering effects of schizophrenia - which then brings us to anxiety and depression."

Smokers have long reported that cigarettes simultaneously calm them down and pep them up, which is one reason researchers are now investigating a relationship between those mood states and nicotine. One of them is Khandra Tyler, a graduate student in the lab of Yousef Tizabi at the Howard University School of Medicine in Washington, DC. In studies with Wistar-Kyoto rats, an animal model of depression, she has reported significantly reduced immobility (a measure of rat depression) in rats dosed with nicotine for nine days - the same effect researchers see when the rats get standard antidepressant drugs.

"My goal was to look and see if nicotine had an antidepressant effect in these animals," Tyler said. Having shown that, she now has turned her attention to the rats' prefrontal cortex. "I'm trying to pinpoint a brain region of interest and trying to uncover a possible theory of how this may be happening."

"We have this entire new receptor system in the brain that we really haven't quite figured out how to take advantage of," said Vermont's Newhouse. "Think of this as like where they were with benzodiazepines in the early '60s.

"The possibility exists that we're on the threshold of a whole new way of influencing how the brain functions with this whole new class of drugs," he explained. "Nicotine modulates the activity of a lot of other receptor systems and brain circuits and so it offers opportunity to tune brain circuits to get the kinds of effects you want."

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See also:
Nicotinic receptors and hippocampal synaptic plasticity ... it's all in the timing
[Research news]
Daniel S. McGehee
Trends in Neurosciences, 2002, 25:4:171-172

Nicotinic receptors in wonderland
[Research news]
Thomas Grutter, Jean-Pierre Changeux
Trends in Biochemical Sciences, 2001, 26:8:459-463

Neuronal nicotinic receptors: No smoke without fire!
David Lodge
Trends in Neurosciences, 2001, 24:132-133

Neuronal nicotinic acetylcholine receptors: From structure to therapeutics
[Meeting Report]
Francesco Clementi, Diego Fornasari, Cecilia Gotti
Trends in Pharmacological Sciences, 2000, 21:2:35-37

Nicotine: Not just for cigarettes anymore
[Update]
Susan Wonnacott, Michael J. Marks
Drug Discovery Today, 1999, 4:11:490-492
 

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