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By Sean Henahan, Access Excellence

SAN DIEGO- Nicotine in tobacco form accounts for millions of deaths each year from cancer, emphysema and heart disease. Yet, in certain neurologic and psychiatric conditions, nicotine can have useful therapeutic effects, reported scientists at the inaugural conference of the Society for Research on Nicotine and Tobacco.

"Nicotine has long been a useful tool for researchers interested in probing the nervous system. Although the health risks associated with its intake via tobacco products has tended to tarnish society's view of nicotine, it is important to recognize that nicotine may have therapeutic potential with a number of disease states," noted Ovid Pomerleau, Ph.D., Director of the Behavioral Medicine Program, University of Michigan and President of the SRNT.

Nicotine is one of the most studied of all drugs. At the beginning of the century, the earliest research into neurotransmitters involved the effects of nicotine, indeed the first neurotransmitter receptor identified was the nicotine receptor. Nicotine mimics the actions of acetylcholine and has been shown to modulates many neurotransmitters.

In recent years there has been considerable research into the role of nicotine receptors in the central nervous system in human cognitive functioning. Initial investigations of the effect of nicotinic agents in both normal and diseased individuals has confirmed the importance of the integrity of these systems for normal cognitive functioning, he said.

There is now some intriguing new data suggesting that very low doses of nicotine can have dramatic effects in controlling the symptoms of Tourette's syndrome, a rare neurologic disorder characterized by physical tics and uncontrollable vocalizations which are often filled with obscenities.

Dr. Paul Sanberg of University of South Florida presented a series of case studies showing long-term control of tics, vocalizations and other symptoms following the use of a single nicotine patch. Interestingly, the patients with the most severe symptoms appear to benefit the most.

"Most patients with Tourette's syndrome are treated with a neuroleptic (anti-seizure) agent of some sort, and generally respond well to this approach. But there are a certain number of patients that are not as responsive to neuroleptics and need some further help. Our studies suggest that these patients may be helped by nicotine therapy. A double-blind study of daily patch use is now underway," he said.

There is now also some new data indicating that nicotine can normalize some of the psychophysiological deficits seen in patients with schizophrenia. This may explain the high prevalence of smoking among schizophrenics and could lead to novel therapeutic approaches, reported Robert Freedman, M.D., department of psychiatry, University of Colorado.

"Schizophrenia is among the most puzzling of mental disorders. There is no well-defined neuronal dysfunction and no specific Mendelian pattern of inheritance, although there is evidence of familial clustering. It has been very difficult to pin down what the biological dysfunction is in these patients," he noted.

Having observed that schizophrenics are extremely sensitive to sensory stimuli, Dr. Freedman conducted a series of electrophysiologic studies involving auditory evoked potentials. These studies revealed that, where normal volunteers can inhibit the EEG response to repeated tones, schizophrenics cannot. Further laboratory studies led Dr. Freedman to the conclusion that nicotine receptors were involved in this phenomenon.

"We did not set out to study nicotine, we set out to study schizophrenia. But anyone who spends anytime with schizophrenics soon realizes that they smoke a great deal. Indeed, a much higher percentage of schizophrenics, both male and female, are heavy smokers than in the general population, and they smoke the higher tar brands," said Freedman.

Dr. Freedman then studied the relatives of schizophrenics who were free of mental illness but who did have the evoked potential deficit. He found that having these volunteers chew nicotine gum normalized the EEG response. A subsequent study in schizophrenic patients who were smokers revealed that smoking cigarettes did produce a short term normalization of the EEG abnormality.

Nicotine per se does not appear to offer a useful approach to the treatment of schizophrenia because of the short term effect of the drug and the high risk side effect profile. However, the research does offer some new targets for drug development, and some encouraging work is already underway, he said.

It may be that schizophrenia may be the wrong disease to treat with nicotine, he added. Other forms of psychosis have different responses to cholinergic agents, particularly the manic and senile psychoses, he added.

There is also increasing clinical data supporting a potential role for nicotine in treatment of Alzheimer's disease, reported Paul Newhouse, M.D., University of Vermont College of Medicine.

Alzheimer's disease is characterized by a loss of cholinergic neurons in the basal forebrain with an associated loss of nicotinic receptors. This vulnerable group of cells is critical both for the regulation of cerebral blood flow and cognitive performance. Clinical studies have shown that intravenous administration of nicotine to non-smoking Alzheimer's patients produces significant improvements in long-term recall and attention span, although increases in symptoms of anxiety and depression are also seen.

"We can demonstrate that loss of nicotinic receptors has functional consequences for cognitive processes and that nicotine agonists appear to provide improvements. This suggests that therapeutic stimulation with nicotinic agonists might have benefits, either in Alzheimer's disease, or in other dementias where nicotinic receptor loss has been observed.

"Where Alzheimer's disease is concerned, a small effect on cognitive function is a positive thing. Even the best cholinergic drugs now on the market produce quite small effects on cognitive function. No one pretends that nicotine agonists are likely to produce a cure for this disease, but I think they may form part of a therapeutic package," said Dr. Newhouse.

A number of Alzheimer's disease studies are currently underway evaluating the nicotine patch approach. In addition, research is underway to develop potential new nicotine agonist therapies targeted at specific nicotine receptor subtypes, with the goal of creating the beneficial effects seen with nicotine without the toxic side effects.

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