Cigarette smoking is the leading cause of premature deaths in the United States. Nicotine has been identified as the principal addictive component in tobacco smoke driving this pathological behavior. To achieve its effects, nicotine interacts with a family of specific membrane components that function as receptors for the naturally occurring neurotransmitter acetylcholine (ACh). It is now clear that so-called nicotinic receptors exert multiple effects at the cellular level and participate in a variety of higher order brain functions; the receptors have also been implicated in a number of neurodegenerative diseases. In addition to excessive activation of the receptors, chronic nicotine exposure can impose long-term regulatory effects on them. The physiological consequences of these effects represent pressing biomedical questions that remain unanswered.
One of the most interesting and abundant nicotinic receptors in brain is a species composed of subunits called the 7. Recent results indicate that 7 receptors perform a host of functions in the nervous system, including the modulation of electrical signals at synapses and the developmental regulation of calcium-dependent events in neurons. The receptors are known to be widely distributed throughout the cortex of the brain. The present experiments employ an animal model to examine the properties of 7 receptors in the mammalian brain, to determine their significance for signaling, and to elucidate the impact of chronic nicotine exposure both on receptor function and on the neuronal circuits in which the receptors participate. The experimental approaches will combine electrical recording techniques, biochemical binding experiments, and fluorescence imaging.
The expected results will provide new information about the physiological significance of 7 nicotinic receptors in the cortex of the brain, and will indicate the kinds of compensatory changes expressed by cortical neurons to mitigate the prolonged excessive stimulation produced by chronic nicotine exposure. This information may also be of value in the search for therapeutic strategies to combat the cortical effects of nicotine. One strategy may be the design of appropriate drugs for targeting the receptors and influencing their activity levels in desired directions for either negating or overcoming the changes caused by tobacco usage. |