T. K. Booker Postdoctoral Fellow Joined the lab in Apr 1999. Ph.D., Pharmacology, University of Colorado, CO (1998) Tel. (858) 453 4100 x1172 Email: booker@salk.edu

Examining the role of various nicotinic acetylcholine receptors in the brain.

The epidemic of tobacco use in industrialized societies is driven by the desire to feel the effects of nicotine. It is likely that the behavioral effects of nicotine are mediated by the electrophysiological responses of the nicotinic cholinergic receptors to nicotine. We have proposed that chronic exposure to nicotine results in desensitization or inactivation of the nicotinic receptor. We postulate that this alters a biochemical pathway, which leads to an increase nicotinic receptor protein. When nicotine is withdrawn, the resulting excess of nicotinic receptor function produces an imbalance in brain function and unpleasant side effects. These leads the smoker to self medicate by smoking another cigarette to inactivate the excess nicotinic receptor activity and return to a feeling of normalcy.

The effects of nicotine are mediated primarily via activation of nicotinic acetylcholine receptors, which belong to a large family of ligand-gated ion channels. These receptors are formed by the assembly of five subunits in a ring to form the ion pore. Genes for 11 different nicotinic subunits (alpha2-9 and beta2-4) have been identified in the brain, providing a vast number of potential combinations of subunits to form different subtypes of nicotinic receptors. When combinations of subunits were expressed in Xenopus oocytes, each receptor subtype displays distinct physiological and pharmacological properties. These results predict a potential for many diverse effects of nicotine in the brain, however which subtypes are actually expressed in specific brain regions and what role each subtype plays is yet unclear. There is emerging evidence that some nicotinic receptors can be postsynaptic and mediate cholinergic transmission. A large body of evidence indicates that other subtypes of nicotinic receptors play a modulatory role by influencing the release of neurotransmitters. Activation of presynaptic nicotinic receptors can elicit the release of many different neurotransmitters. Data indicate that different subtypes of nAChR may mediate these responses, however, the subunit composition of those receptors is not well understood.

Our current work seeks to test the hypothesis that we have proposed to explain nicotine dependence, that is, that chronic exposure to nicotine induces a regulatory process(s) that depresses nicotinic receptor function. Evidence suggests that different subtypes of nAChRs in the brain play multiple and diverse roles; determining the physiological significance of various subtypes will help us identify specific receptors involved in the development of nicotinic tolerance. Ligands that recognize different subtypes of nicotinic receptors with specificity are largely unavailable, so we are using genetic approaches to study the subunit composition of different subtypes of nicotinic receptor in the brain. We are using homologous recombination techniques to delete the gene encoding a nicotinic receptor subunit, thus generating mutant mice in which that subunit has been deleted and then examining the consequences of the loss of the subunit by various biochemical, electrophysiological and behavioral assays. With more detailed knowledge about the role of nicotinic receptors in brain function, it might be possible to develop drugs that would help patients overcome their nicotine addiction. Such a drug development program may also provide leads to therapeutics for the treatment of Alzheimer's disease, Parkinson's disease and various mood disorders.