Nicotine Metabolite May Improve Memory, Protect Against Disease

"These findings don't mean people should smoke," warns neuroscientist Michael Kuhar, PhD, of Emory University. "Any benefits from the nicotine in cigarettes or other tobacco products are far outweighed by the proven harm of using those products. But pure nicotine-like compounds as medications do show promise for treating human disorders."

New studies continue to report on the dangers of smoking. One such study suggests that mothers who smoke during pregnancy may be putting their children at risk of having emotional learning problems that last into adulthood. Another study indicates that when smoking is taken up in adolescence, it also produces long-lasting effects on brain development -- effects that interfere with learning and memory.

The children of women who smoke during pregnancy have been found to be at greater risk for a wide variety of emotional and behavioral disorders, such as attention deficit hyperactivity disorder (ADHD) and conduct disorder. Now, new animal studies from the Yale University School of Medicine demonstrate that the effects of developmental nicotine on emotional learning last into adulthood.

"If we can identify the mechanism for this long-term behavioral change, we may be able to develop new therapies for human emotional disorders that are linked to prenatal nicotine exposure," says Sarah King, PhD.

For their most recent study, King and her colleague, Marina Picciotto, PhD, used an animal model of emotional learning known as passive avoidance. This model measures how long an animal avoids a dark chamber in which it had previously received a mild electric shock. King and Picciotto found that nicotine-treated mice showed a hypersensitive response and avoided the dark compartment longer than non-exposed mice.

This response was identical to one the researchers had reported on previously (Journal of Neuroscience, May 2003) in genetically altered mice that lack high affinity nicotine receptors as a result of a knockout mutation. "We believe that nicotine exposure during development-- the same kind of exposure that occurs in mothers who smoke during pregnancy -- disrupts normal nicotine receptor activity, much like the knockout mutation, and that this leads to altered emotional learning in adulthood," says King.

King and Picciotto have also identified a novel brain circuit -- glutamate neurons, which originate in the cortex and project to the thalamus (corticothalmic neurons) -- as the likely site where changes occur in the brain during early nicotine exposure. They are currently working to identify the molecular changes that developmental exposure to nicotine triggers in the corticothalamic neurons.

Each year, about 2 million teenagers become regular smokers, according to the American Lung Association. Because the brain continues to develop during adolescence -- and beyond -- scientists at George Mason University decided to investigate the effect that exposure to nicotine during adolescence has on later behavioral functioning. The researchers implanted 46 rats with small minipumps that dispensed either 3 or 6 mg of nicotine per kilogram of body weight per day -- or no nicotine at all (controls). When the animals reached adulthood, they were tested for spatial learning and memory.

Nicotine made a significant difference in the animals' performance in the tests. Low and high doses of nicotine altered behavior in opposite directions: The low-dose group tended to learn faster and the high-dose group tended to learn slower than the control animals. "Whether performance improved or declined is probably less important than the demonstration that nicotine does produce long-lasting changes in the animals' performance, presumably reflecting long-lasting effects on brain development," says Robert Smith, PhD.

Although this research was done in rats, the processes of brain development are similar in humans, which leads Smith to believe that teenagers who smoke aren't risking only addiction, but also lasting changes in the development of their brains. Smith and his colleagues are now examining the genetic mechanisms that are involved in producing this lasting change in behavior.

During times of stress, smokers tend to increase the number of cigarettes they light up -- perhaps as a form of self-medication to counteract the harmful effects of stress on the brain. Stress, which may range from mild anxiety to posttraumatic stress disorder, has been shown to impair normal brain function, including learning and memory.

Researchers in the laboratories of Karim Alkadhi, PhD, at the University of Houston College of Pharmacy recently studied the effect of nicotine on stress-induced memory impairment in rats. They found that when stressed animals were given nicotine, they performed significantly better at short-term memory tests than stressed animals not given the chemical. In fact, the nicotine-treated stressed animals performed the same as unstressed (control) animals.

"Our findings are important to the understanding of the mechanism by which nicotine repairs stress-damaged brain function," says Abdulaziz Aleisa, a doctoral student at UH. "This research may eventually help in the designing of new, safe approaches to the treatment of Alzheimer's and Parkinson's diseases -- approaches that mimic the beneficial effect of nicotine on stress."

In other studies, another doctoral student, Karem Al-Zoubi, and his colleagues have found that nicotine may improve some of the learning and memory problems associated with hypothyroidism, a common disorder in which the thyroid gland makes inadequate amounts of thyroid hormones. These findings add to the understanding of the mechanism by which nicotine repairs damaged brain function, and may one day help scientists design new, safe therapeutic agents for hypothyroidism and other conditions that cause brain impairments.

An estimated 5 million Americans have hypothyroidism, which produces a variety of symptoms, including such mental impairments as cloudy thinking, inability to concentrate, and memory problems. The elderly, particularly women, are more likely to develop the disease. Up to 10 percent of women over age 50 and up to 1.25 percent of men over age 60 have a defective thyroid gland that puts out less-than-adequate amounts of thyroid hormone in the blood. The condition can also strike infants and children, where its effects can be very serious. One in 4,000 babies are born with hypothyroidism. In infants, the condition often results in severe developmental problems, including mental retardation, and is referred to as cretinism.

To study the effect of nicotine on hypothyroidism, the researchers surgically removed most of the thyroid gland from a group of rats. They then treated some of those rats twice daily with a dose of nicotine that produced blood nicotine levels equivalent to those seen in the blood of smokers. All the animals were then given a test that has both learning and a memory phase.

The nicotine-treated hypothyroid animals made significantly fewer errors on both phases of the test than the untreated hypothyroid animals. In fact, the treated hypothyroid animals had a similar error rate to an untreated control group with normal thyroid glands and a nicotine-treated group with normal thyroid glands.

"Nicotine appears to repair learning and memory deficits caused by hypothyroidism, although it doesn't appear to improve learning and memory in normal animals," says Al-Zoubi.

The group is now working to uncover the means by which stress and hypothyroidism produce mental deficits and how nicotine corrects these deficits.

Cotinine, the primary breakdown product (metabolite) of nicotine, shows promise for improving memory and for protecting brain cells from diseases such as Alzheimer's and Parkinson's -- but perhaps with less addiction and other side effects of nicotine, report scientists from the Medical College of Georgia. The researchers have also found that, in animal studies, the properties of cotinine may be helpful in treating the debilitating psychotic behavior of people with schizophrenia.

Up to now, cotinine's biggest use has been as a urine marker for tobacco use, although its potential use in curbing smoking also has been explored.

"Many people have thought that cotinine was an essentially inactive metabolite, but we have shown that at appropriate doses, it enhances memory and protects brain cells from dying, as well as having anti-psychotic properties," says Jerry Buccafusco, PhD.

Buccafusco became interested in studying cotinine after observing in studies that monkeys continued to derive memory benefits from nicotine long after the chemical had left the body. Nicotine is rapidly metabolized, and has a half life of about one hour. Cotinine is metabolized at a much lower rate; its half life is about 24 hours.

In one of their current studies, Buccafusco and his colleagues gave both young and old monkeys cotinine, then tested the animals' memory skills. The monkeys that received cotinine did better on the tests than those that didn't receive the metabolite --results similar to those that Buccafusco has found with nicotine.

The researchers also studied cotinine's effect on neuron-like cells in culture. They used a model in which growth factor is taken away from the cells so that they start to die, just as they do in neurodegenerative diseases such as Alzheimer's. "We were surprised to find that cotinine was as effective as nicotine at preventing cell death," says Buccafusco.

In further studies involving rats, Buccafusco and his colleagues discovered that cotinine was as effective as standard anti-schizophrenic drugs in reducing the startle response -- the natural reaction to a loud noise. Normally, rats -- and people -- are startled by loud noises. If a less intense noise consistently precedes the loud one, however, the startle response tends to weaken -- but not in people with schizophrenia or in laboratory animals given schizophrenic-producing drugs.

"Cotinine was nearly as effective as a standard clinically used anti-schizophrenic drug in reversing this response," says Buccafusco. "This finding holds tremendous promise for patients suffering from schizophrenia since the drugs currently being used to treat this illness are often associated with severe long-term neurological side effects, such as parkinsonian-like tremors and memory problems."