Dispelling the Myths About Addiction Strategies to Increase Understanding and Strengthen Research (1997) / Chapter Skim
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Appendix D
Appendix D
Pages 169-176
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From page 169... ...
I surveyed the alcohol research community in the United States and learned that no one was exploiting the power of molecular and cellular neuroscience to investigate alcoholism. Therefore, I decided to develop a program designed to uncover fundamental molecular mechanisms of intoxication, tolerance, and dependence with the expectation that this information would lead to new therapies for alcohol addiction and alcoholic neurologic disorders.
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From page 170... ...
Therefore, blood alcohol levels accurately reflect brain alcohol concentrations. Alcohol is a sedating agent and, when blood levels reach 500 mg percent, naive individuals can become comatose and even die because of respiratory depression.
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From page 171... ...
He discovered that neural cells in culture adapt to ethanol by increasing the concentration and activity of voltage-dependent calcium channels. Ordinarily, ethanol inhibited calcium flux through these channels, but when ethanol was removed from the cells, the increased concentration of channels mediated a tremendous increase in calcium flux during alcohol withdrawal.
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From page 172... ...
We found that long-term exposure to ethanol caused a selective reduction in gene expression for Gorse and thus decreased production of GaS mRNA and protein. This accounts for heterologous desensitization of signal transduction.
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From page 173... ...
A theme emerging from our work and other laboratories doing alcohol research is that the primary targets of ethanol involve regulatory mechanisms, such as protein kineses and protein phosphatases. As a result, we began to think about protein kinase A and how it might be regulated by exposure to ethanol.
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From page 174... ...
The long-term consequences of adaptive changes involve changes in gene expression, which probably underlie the development of complex abnormalities such as addiction and alcoholic neurologic disorders. Moreover, changes in gene expression may help to answer a puzzling question in alcohol research: How is it that short-term exposure to alcohol produces functional and metabolic changes whereas long-term exposure causes structural pathology and disease?
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From page 175... ...
Moreover, it is also possible to use available mutants as controls to prove that ethanol sensitivity is mediated by the nervous system and not due to an artifact. Perhaps this is best illustrated by the frequently asked question whether ethanol metabolism contributes to prolonged intoxication and increased sensitivity.
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From page 176... ...
Think of the potential of this strategy: not only is it possible to identify genes that mediate normal and abnormal CNS responses to ethanol, it will be possible to test candidate genes in Drosophila derived from other systems to determine whether they contribute to ethanol-induced changes in neural function. In addition, genes identified in Drosophila can be used to identify genes in human beings.
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