It is almost certain that the reinforcing effects of ethanol arise from a summation of its effects on a number of protein targets, likely including neurotransmitter receptors and ion channels. It would be highly beneficial for the treatment of alcoholism if these positively reinforcing effects of alcohol could be antagonized by chemical means and if novel anti-alcoholism compounds could be identified and developed rationally. Until recently, however, medication development for the treatment of alcoholism has largely occurred serendipitously. Rather than continuing to rely on serendipity for the discovery of new compounds to combat alcoholism it seems logical rather to attempt reasoned approaches in the identification of compounds that affect the functioning of protein targets that are believed (or that at least could) play roles in the reinforcing effects of ethanol. The research proposed in this P01 project application will use phage display to identify peptides that selectively interact with specific heteromeric ?/? glycine receptors. These peptides will be assayed functionally on glycine receptors expressed in Xenopus oocytes and the most promising will also be studied for their effects on dopamine cell firing in ventral tegmental area slices. They will also be tested for their effects on alcohol consumption and preference by the Behavioral Core. Based on the many different small molecules that are known to affect the functioning of receptors and ion channels (egs., polyamines, metals and benzodiazepines) there is a strong rationale to support the idea that specific peptides can be identified that could affect the functioning of specific glycine receptor subtypes. The glycine receptor was chosen as our initial molecular target because it fulfills all of the following criteria that we consider important for protein targets of potential interest: (1) it is a protein for which a substantial amount of evidence has been accumulated regarding its importance for alcohol actions in vivo;(2) it exhibits considerable sensitivity to the effects of alcohol when assayed in vitro;(3) we have expertise in the study of its function electrophysiologically, and (4) we have obtained considerable preliminary data validating our experimental approach in identifying novel specific allosteric modulators at the glycine receptor.
It is the purpose of this project to identify novel molecules that can affect the functioning of cell-surface proteins thought to be significant mediators of the effects of ethanol in vivo. The ultimate goal is the eventual development of compounds that can antagonize the reinforcing properties of alcohol, thus decreasing ethanol consumption in alcoholics. This rational approach to drug discovery contrasts markedly with the serendipitous approach to the discovery of drugs currently used in the treatment of alcoholism.
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