Project 1 - Chemistry & In Vitro Studies of Chinese Herbal Remedies

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Alcohol and drug abuse pose serious medical, social, and economic problems in the United States and around the world. A great deal of effort has been directed toward developing effective therapies. Unfortunately, in the last 40 years, only three medications with limited efficacy have been approved by the U.S. Food and Drug Administration. The complexity of cocaine dependence and the lack of effective remediation, especially for relapse, which is often precipitated by withdrawal and/or intense craving even after prolonged abstinence, poses a serious therapeutic challenge. One possible mechanism of action underlying the modification of cocaine's behavioral effects by herbal remedies is through kappa opioid receptors. Because many herbal remedies that were originally developed during the 18th and 19th centuries in China were targeted at opium addiction, chemical fractions that will be screened in Project 1 for kappa receptor activity may be found to have kappa agonist or antagonist actions. It is well established that some abuse related effects of cocaine can be modified through kappa opioid receptors, and these effects have been related to kappa opioid modulation of dopamine levels in the nucleus accumbens. For example, in rats, kappa opioid agonists have been shown to attenuate cocaine-stimulated locomotor activity, cocaine discrimination and cocaine self-administration. Moreover, kappa opioid agonists have also been shown to attenuate cocaine-induced increases in extracellular levels of dopamine in the nucleus accumbens. In addition, recent studies also indicate that kappa antagonists may be useful in preventing relapse to opioid and cocaine use. Therefore, a consortium effort focusing on alternative pharmacotherapies would have important clinical significance, especially in preventing relapse. We selected two Chinese herbal medicines, YGT (NPI-025) and XJL (NPI-028), for this project because of their proven efficacy in the treatment of substance abuse in China and encouraging scientific data obtained in recent years in our laboratories. The specific aims of this Research Project 1 are (1) to procure and standardize these two herbal medicines by HPLC fingerprinting; (2) to provide purified components by fractionation as internal standards and as molecular tools to elucidate the mechanism of action; (3) to distribute these standardized herbal medicines and fractions to Research Projects 1, 2, and 4 for in vitro, in vivo, and clinical evaluations respectively; and (4) to conduct in vitro screening of Chinese herbal remedies and fractions for their affinity at the mu, delta and kappa opioid receptors, the nociceptin / orphanin FQ (N/OFQ) receptor and D1 and D2 dopamine receptors and for their receptor functions by [35S]GTPgammaS binding and adenylyl cyclase activity. The herbal medicines or fractions that show positive results in vitro will be examined in Project 2 using various in vivo models. Only those with the best in vivo activity will be subiect to clinical evaluation in Project 4.