Alcohol intoxication is the greatest contributing factor to transportation fatalities in the United States. Alcohol's (EtOH) major pharmacological target is GABAA receptors (GABAAR). The goal of our research is to develop novel anti-alcohol drugs, which may reduce alcohol-related transportation fatalities. Alcohol consumption enhances GABAAR function and induces GABAAR plasticity. Hovenia, an herbal medicine, has been used in Asia to treat alcohol dependence safely and effectively for more than a millennium. We have demonstrated in pilot studies that Hovenia can reduce EtOH intoxication and block the changes in GABAAR subunit 14 and 11 peptide levels after EtOH intoxication in rats. We showed that Hovenia enhances GABAAR-mediated inhibitory synaptic and extrasynaptic currents in hippocampal neurons in brain slices in vitro. We have identified the active constituents in Hovenia and their chemical structures. Hovenia-dihydromyricetin (H-DHM) is the major component (pilot studies) of the active constituents. The purpose of this application is to study the cellular mechanisms of H-DHM interactions with EtOH and GABAARs. We will pursue these specific aims:
Specific aim 1) To determine H-DHM effects on synaptic and extrasynaptic GABAAR function, whole cell-patch recording of hippocampal neurons in brain slices will be performed in vitro. Dose-response studies of H-DHM interactions with GABAARs and EtOH will be conducted using our standard electrophysiological and pharmacological techniques.
Specific aim 2) To determine H-DHM effects on acute EtOH intoxication, selected behavioral measurements will be performed in vivo. Rotarod performance will provide a measurement of coordinated movement. Elevate plus maze will be used to evaluate anxiolytic effects. The LORR assay will be able to evaluate sedative/anesthetic effects.
Specific aim 3) To determine H-DHM effects on EtOH pharmacokinetics. These studies are necessary because literature suggests that herbal medicines for alcohol intoxication act to reduce alcohol absorption on the gut, or increase metabolism, thus lowering blood alcohol levels. The novelty of this application is testing H-DHM from Hovenia as a potential treatment for alcohol intoxication and alcohol dependence as well as to elucidate the cellular mechanisms underlying the therapeutic effects of H-DHM. By the end of this grant period, we will understand how H-DHM interacts with GABAARs and EtOH to block EtOH intoxication-induced plasticity, and the resultant EtOH-induced behavioral changes. Understanding the effects of H-DHM in acute alcohol intoxication will provide a pharmacological basis for developing a novel anti-alcoholic therapy that might decrease alcohol-related transportation fatalities.
Motor vehicle collisions are the leading cause of transportation fatalities in the nation and alcohol is the primary factor contributing to the fatalities. The goal of our project is to understand the cellular mechanisms underlying the therapeutic effects of the active in gradient H-DHM on acute alcohol intoxication and alcohol dependence so as to develop a novel anti- alcohol intoxication drug that can prevent alcohol-related transportation fatalities.
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