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Enzyme &Receptor Antagonists of GHB, GBL &1, 4-BD

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The widespread abuse of gamma-hydroxybutyrate (GHB) and its chemical precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), has resulted in escalating episodes of life-threatening acute overdoses. Because abuse of GHB and its precursors is a recently evolving phenomenon, treatment strategies for acute overdoses are currently limited. The objectives of this proposal are to address two specific research areas solicited in the request for application (DA-01-014, "Research on GHB and Its Precursors") issued by the National Institute on Drug Abuse (NIDA): 1.) overdose and toxicity of GHB and its precursors, and 2.) treatment strategies for GHB and its precursors. Although GHB and GBL were made illegal by the Hillary J. Farias and Samantha Reed Date Rape Prohibition Act of 2000 (the former is now a federal schedule I drug, and the latter is a federal list I chemical), 1,4-BD is currently recognized as a Class I Health Hazard (a potentially life-threatening hazard). This designation imposes no legal restrictions on the manufacture, distribution (in dietary supplements), or possession of 1,4-BD. Increasingly, 1,4-BD has been responsible for severe life-threatening overdoses and deaths. Thus, our laboratory has prioritized and focused its research efforts on 1,4-BD, which is currently the only legally available GHB-related drug. Additionally, 1,4-BD is the only GHB-related drug that can directly interact with ETOH, the most commonly coingested substance with GHB-related drugs, leading to dangerous interactions. Furthermore, its complete biotransformation to GHB permitted us the unique opportunity to study indirectly GHB's interactions with ETOH and GABA-B and GHB receptors.

This application has three specific research aims. The first aim is to characterize 1,4-BD and GHB toxicity after acute overdoses. The second aim is to study potential interactions of 1,4-BD and GHB with ETOH. The third aim is to investigate potential antidotes for acute 1,4-BD overdose and combined acute 1,4-BD and ETOH overdose. Potentially effective antidotes exist for 1,4-BD, specifically, and for GHB, GBL, and 1,4-BD collectively. The antidote for 1,4-BD specifically is an enzyme antagonist of alcohol dehydrogenase (4-methylpyrazole, Antizol), which may block in vivo enzymatic biotransformation of 1,4-BD to GHB. The antidotes for the GHB, GBL, and 1,4-BD collectively are receptor antagonists of GABA-B receptors (CGP-35348) and GHB-specific receptors (NCS-382), the sites of pharmacologic action of GHB, GBL, and 1,4-BD. In general, a murine model (CD-l mice) will be used to assess the acute effects of 1,4-BD, GHB, and ETOH on behavioral (open field locomotion test), neuromuscular (righting reflex, rotarod test, grip strength test), and biochemical processes (blood 1,4-BD and GHB levels). This murine model will also be used to study the effects of potential therapeutic agents for acute overdoses. The results of this study will expand upon promising data from pilot studies performed in this laboratory on acute 1,4-BD and GHB toxicity as well as novel therapeutic agents for its potential medical management.

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