Nicotonic receptors: role in addiction and reproduction
Abstracts
Initial Award Abstract |
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The epidemic of tobacco use in industrialized societies is driven by the desire to feel the effects of nicotine and it is likely that the behavioral effects of nicotine are mediated through nicotine receptors. It is now clear that the reason people smoke tobacco is to deliver nicotine to the brain. The use of cigarettes to deliver nicotine has led to an epidemic of lung cancer and heart disease in the United States and increasingly in many other countries and is a major cause of bad health. Indeed smoking is the major preventable cause of poor health in the United States. The purpose of the proposed research is to contribute to a molecular and neurobiological understanding of nicotine dependence and addiction to enable the development of rational strategies to help people stop smoking. It is anticipated that this knowledge will lead to the design of better behavioral approaches and new therapeutic drugs to combat the smoking epidemic.
As is the case for chemical dependence in general, the mechanism of nicotine dependence is not known. To develop a rational theory of nicotine dependence it is necessary to understand how nicotine exerts its effects on the nervous system. During the past few years a large family of nicotinic receptors has been discovered in the brain. This discovery has revolutionized the way this excitatory receptor system is now viewed, and may explain the powerful and diverse consequences of nicotine. These receptors mediate normal communication between nerve cells in the brain. Nicotine causes abnormal function of these nicotinic receptors interfering with the normal communication between nerve cells. We have proposed that long term exposure to nicotine changes the properties of nicotinic receptors in the brain and that this could underlie the molecular mechanism of dependence. The overall goal of this research proposal is to test the proposition that chronic exposure to nicotine induces a regulatory process which depresses nicotinic receptor function. This hypothesis will be tested by looking for novel proteins which regulate nicotinic receptor function. A genetic screen will be used to search for new proteins induced in the brain by chronic exposure to nicotine and which associate with and regulate nicotinic receptor function.
Nicotine has profound effects on hormone secretion which may contribute to many of the serious health problems associated with smoking, such as infertility, immune suppression and arteriosclerosis. The role of nicotinic receptors in the regulation of hormone secretion will be studied. |
Final Report |
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The epidemic of tobacco use in industrialized societies is driven by the desire to feel the effects of nicotine and it is likely that the behavioral effects of nicotine are mediated by the electrophysiological responses of the nicotinic cholinergic receptors to nicotine. It is now clear that the reason people smoke tobacco is to deliver nicotine to the brain. The use of cigarettes to deliver nicotine has led to an epidemic of lung cancer and heart disease in the United States and increasingly in many other countries and is a major cause of bad health. Indeed, smoking is the major preventable cause of poor health in the United States. The purpose of this research is to contribute to a molecular and neurobiological understanding of nicotine dependence and addiction to enable the development of rational strategies to help people stop smoking. It is anticipated that this knowledge will lead to the design of better behavioral approaches and new therapeutic drugs to combat the smoking epidemic. The mechanism of nicotine dependence is not known and to develop a rational theory of nicotine dependence it is necessary to understand how nicotine exerts its effects on the nervous system. During the past few years a large family of nicotinic receptors has been discovered in the brain and revolutionized the way this excitatory receptor system is now viewed, and may explain the powerful and diverse consequences of nicotine. These receptors mediate normal communication between nerve cells in the brain. We have proposed that long-term exposure to nicotine changes the properties of nicotinic receptors in the brain and that this could underlie the molecular mechanism of dependence, since the abnormal function of these nicotinic receptors would interfere with the normal communication between nerve cells. The goal of this research is to test the idea which we have proposed to explain nicotine dependence, i.e. that chronic exposure to nicotine induces a regulatory process which depresses nicotinic receptor function (Dani and Heinemann, Neuron, 16, 905-908, 1996). This hypothesis is being tested by looking for novel proteins, which regulate nicotinic receptor function.
A genetic screen has been used to search for proteins that associate with nicotinic receptor and potentially could regulate nicotinic receptor function during exposure to nicotine. Using a genetic screen we have identified the products of two genes that interact with one of the major nicotinic receptors expressed in the brain. One of the genes codes for a protein known to be a regulator of signaling pathways within the nerve cells. Thus, this gene could be involved in the regulation of nicotinic receptors and play a role in nicotine addiction. The second gene is a new gene that has no known function. In order to discover the function of this new gene we have isolated the gene and are using genetic engineering to make a mouse with a mutation in the gene. The mouse will be tested for alterations in nicotine induced behaviors.
In the future we plan to test whether or not the genes that we have identified in the genetic screen are part of a nicotinic receptor regulatory mechanism that responds to exposure to nicotine. Identification of nicotinic receptor regulatory proteins may make it possible to develop drugs which reverse the changes that take place in the brains of smokers which may help patients stop smoking. |
