Nicotinic Regulation of GABAergic Inhibition/Excitation
Initial Award Abstract
Nicotine acts on special proteins in the cell membrane called nicotinic acetylcholine receptors to exert its effects on behavior and to produces addiction. Activation of the receptors normally in the brain occurs by interaction with a chemical called acetylcholine. It is known that these receptors can have multiple effects at connections in the brain called synapses. But the larger significance of these effects, i.e. what the effects mean for brain function, is poorly understood.
We have obtained preliminary evidence that exposing brain cells to nicotine can have a profound effect on another signaling pathway not previously recognized. This pathway involves the brain chemical GABA which acts as the main "inhibitory" signal in the brain. GABA causes circuits and pathways to be more inhibited, i.e. to quiet down. Our preliminary evidence is that nicotine exposure can transiently change the gradient of chloride ions across the cell outer membrane. It has long been known that the chloride gradient determines the effect of GABA. The changes that nicotine causes in the chloride gradient are likely to make the GABA responses temporarily excitatory. If these initial results extend to nicotine concentrations found in smokers and if the phenomenon is widespread, the findings will have tremendous import for understanding the mechanisms by which nicotine achieves its effects.
Two Specific Aims are proposed here. The first is designed to examine the extent to which nicotine controls the chloride gradients underlying GABA responses in adult brain cells. The second aim employs functional assays to demonstrate directly that nicotine can generate GABA-mediated excitation in adult brain cells. Lastly experiments will test the hypothesis that the nicotine-induced change in GABA-mediated signaling can produce transient hyperexcitability in adult brain circuits.
The experiments proposed here are likely to reveal a major action of nicotine in the brain, one that has not previously been suspected, let alone documented. The results will provide new insight into how we think about nicotinic modulation of behavior, and, on a larger scale, the kinds of mechanisms available for altering information processing. Biomedically the results will have the value of identifying new consequences and sites of action for nicotine, raising awareness about the consequences of tobacco consumption and possibly identifying new targets for pharmaceutical intervention. |