The abuse of cocaine is widely recognized to be an extremely serious health and social problem of epidemic proportions for which there is no effective treatment. This problem continues to be exacerbated by cocaine base ("crack") smoking, an extremely reinforcing and dependence producing route of self-administration. Our approach to treatment and prevention of cocaine abuse involves development of high affinity, slowly dissociating, low intrinsic activity cocaine receptor agonists. This approach has been validated with our finding that the lead compound GBR 12909 prevents cocaine self-administration in rhesus monkeys trained to self-administer cocaine with no effect on normal behavior as measured by food maintained responding. Studies with repeated administration of drugs from our chemical synthesis program and GBR 12909 have shown sustained therapeutic effects on cocaine self administration. For example, in a 12 day treatment study with GBR 12909, cocaine self-administration was eliminated in monkeys with no effect on food intake. No evidence for development of tolerance (diminishing activity of the treatment drug) was observed. When the treatment drug was discontinued after 12 days, cocaine self- administration returned to the pretreatment level but could again be eliminated by renewed GBR 12909 treatment. Food-maintained responding was used as a "control" for unwanted, behaviorally-impairing, side effects of test agents. These selective effects were unlike those of d-amphetamine or long-acting cocaine analogs (e.g. CFT) suggesting that selective GBR 12909 and related DA reuptake inhibitors do not simply substitute for the properties of cocaine responsible for its abuse potential. Taken together, our studies indicate GBR 12909 as well as drugs synthesized in our program with this profile are potentially valuable agents for the treatment and prevention of human cocaine abuse. Opiate receptors play major roles in analgesic and euphoric effects of opiate drugs. Recent cloning of cDNAs encoding the rodent and human mu receptor have opened up new opportunities for research m opioid pharmacology and revealed high homology between the predicted receptors but also some sequence differences. Our ligand selectivity profiles of the human and rat mu receptors revealed modest differences in affinities for morphine and naloxone in COS but not CHO cells. Interesting differences between these data and data previously obtained with the peptide agonist [3H]DAMGO suggest that peptide and alkaloid agonists may label different domains of the mu receptor.