Mechanism of drug addiction

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DESCRIPTION (provided by applicant): Our long-term goal is to understand the mechanism of drug addiction and to contribute to finding cures for this and other mental disorders. The transporters for dopamine, serotonin, and norepinephrine (DAT, SERT, and NET) are the high affinity targets for cocaine, amphetamines and several important therapeutic drugs treating mental disorders. It was hypothesized and generally accepted that the addictive property of cocaine is mediated predominantly by DAT. This hypothesis has been based on indirect evidence. Our specific aims are 1) to clone biogenic amine transporters from diverse species and to study structural basis of transport properties. 2) to identify regions or residues in the cloned transporters that are involved in cocaine binding and to study the nature of the binding interactions, and 3) to engineer a mutant DAT that is functionally similar to wild type (wt) mouse DAT (mDAT) but with a substantial shift in cocaine sensitivity. Our future aims are to generate transgenic mice bearing a mutant DAT with a shift in sensitivity to cocaine and to determine the role of DAT in cocaine-induced responses. Over millions of years of evolution, nature has generated a large number of functional transporter variants exhibiting differences in transport properties and in the sensitivity to cocaine and other drugs providing clues to the residues responsible for the differences. We will clone DAT, SERT, and NET from diverse species including a caterpillar pest of coca plant by polymerase chain reaction using the sequence information of known transporters. We will identify residues involved in various aspect of transport function and in binding cocaine and other drugs by comparing cloned transporters. We will make specific and random mutations at and near the residues that are involved in cocaine binding and screen for functional mutants that are significantly less sensitive to cocaine. Transgenic mice bearing mutant DAT will allow us to test the role of DAT in drug addition. A clear understanding of how transporters function, how and where drugs bind to the transporters, and the role of DAT, SERT, and NET in drug addiction is important for developing new and more effective treatments for drug addiction and other mental disorders.