Despite an apparent trend towards the reduced use of some drugs, recent surveys suggest that the abuse of opioids (e.g., heroin) is increasing. Public health issues associated with opioid abuse are far reaching and complex, principally because there is a strong association between illicit opioid use and the incidence of acquired immunodeficiency virus (AIDS) as well as other diseases (e.g. hepatitis B). Among the many approaches that have been put forth in an attempt to reduce illicit opioid use are pharmacological strategies that consist of either blocking the positive subjective (euphoric) effects of opioids, so as to prevent the likelihood of further drug self administration, or replacing the illicit opioid with a safer, alternative drug, so as to reduce the criminal and other (e.g. needle-sharing) behavior that often accompany opioid abuse. Methadone, buprenorphine and naltrexone represent different pharmacological strategies for treating opioid abuse and opioid dependence, and each of these compounds has been demonstrated to be effective in reducing illicit drug use under limited conditions in some abusers. However, in other abusers and other situations, none of these compounds is effective. It is essential, therefore, to continue designing and developing new drugs in order to provide a wider range of pharmacotherapeutic options for the treatment of opioid and other drug abuse. The preclinical assays that were developed during the previous support of this project have provided reliable and highly-quantitative measures of drug action in opioid-treated pigeons and opioid-treated non-human primates, and the experiments proposed in the current application will now use these procedures both to evaluate other potential therapeutic strategies as well as to further explore basic research on relationships between actions of opioids at receptors and their abuse and dependence liability. Drug discrimination procedures will be used to model the subjective effects of dependence and withdrawal in animals treated acutely or chronically with one of various drugs that are selective for (sub)types of opioid receptors. The development of dependence and the modification of withdrawal will be assessed by studying discriminative stimulus effects of mu and kappa receptor-selective opioid agonists and antagonists. The goals of these studies are to: 1) evaluate, using a non-human primate model of opioid dependence, compounds that might be useful in the treatment of opioid abuse (e.g., LAAM, buprenorphine); 2) combine multiple measures of withdrawal (discrimination and disruptions in food-maintained responding) to increase the sensitivity of the assay as well as provide a bridge between two methods for studying drug dependence; 3) use drug discrimination to study the long-term consequences of opioid dependence that might be related to recurrent drug-seeking behavior in ex-abusers; 4) compare the discriminative stimulus effects of drugs to their antinociceptive effects in untreated and in opioid-treated monkeys; and 5) implement and validate modifications on this procedure so as to improve the pharmacological and behavioral sensitivity as well as the predictive value of this preclinical model of dependence. Data obtained with these procedures have demonstrated predictive value for estimating the abuse liability of opioids in humans. Consequently, the dependence potential of opioids as well as interactions among drugs from different classes will provide fundamental new information that can be used in the implementation of treatment programs in human drug abusers as well as in the identification, selection and evaluation of future pharmacotherapeutics.
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