The primary focus of this research is to develop a better understanding of the pharmacological mechanisms underlying the behavioral effects of cocaine that lead to its abuse, and the consequences of that abuse. This better understanding will advance basic knowledge of the pharmacology of cocaine, and drug abuse. Further, the research will have broader implications for the psychology of the motivational processes involved in reinforcement and goal-directed behavior. A better understanding of the pharmacology of cocaine and drug abuse will lead to advances in our discovery of new treatment modalities for cocaine abuse which will ultimately have a positive public health impact in curtailing drug abuse and the transmission of HIV infection. Studies have indicated that: (1) The psychomotor stimulant effects of cocaine, as indicated by increases in locomotor activity, may be mediated by D1-like and D2-like dopamine receptors; however, the stimulation of locomotor activity appears not to be related to agonist activity mediated by D3 dopamine receptors. The roles of D4 and D5 dopamine receptors have not been determined, however, we have new tools for further studies of the D4 dopamine receptor. (2) The subjective behavioral effects of cocaine are mediated by both D1, D2, and D3 dopamine receptor systems, although actions through either system alone are not sufficient to fully reproduce the subjective effects of cocaine in rodents and primates. The role of D4 receptors is currently under study. (3) Behavioral effects of cocaine related to its abuse appear to be mediated by A high-affinity@ binding of cocaine to the dopamine transporter. Low affintiy binding at the dopamine transporter appears to produce effects that are not related to cocaine abuse; i.e. locomotor depression rather than stimulation and discriminative stimulus effects that are different from those of cocaine. (4) Chronic exposure to cocaine produces an up-regulation of the mu-opioid system without changes in delta-mediated function. In addition, there are increases and decreases in prodynorphin gene expression, with increases in caudate-putamen and decreases in hypothalamus. Chronic treatment with selective dopamine uptake inhibitors also upregulated mu-opioid receptors suggesting that inhibition of dopamine uptake is responsible for cocaine=s effect on opioid receptors.(5) Unique compounds based on cocaine structures have been synthesized that provide information on the nature of the interaction of cocaine with its binding site on the dopamine transporter. The results of these studies confirm and extend previous results indicating that steric factors of substitutions at the 2-position of the tropane ring are not as influential in affecting affinity as are electrostatic factors. Electron-rich substituents favor high affinity binding at the dopamine transporter. (6) Benztropine analogs also have affinity for the cocaine binding site. These compounds, however, do not have cocaine-like behavioral effects despite in vitro binding to the dopamine transporter and inhibition of dopamine uptake. Structure-activity studies indicate that the binding of these compounds to the dopamine transporter is different from that for cocaine. Recent studies indicate that the lack of cocaine-like behavioral effects is not due to the actions of these drugs at muscarinic receptors. (7) Rimcazole is a novel dopamine uptake inhibitor that also lacks cocaine-like pharmacological activity. Recent studies have been elucidating the relative affinity of this compound for high- and low-affinity sites on the dopamine transporter. An analog of rimcazole that binds irreversibly to the dopamine transporter has been initially characterized. Further studies with it will be directed at determining functional roles of high- and low- affinity binding in the behavioral effects of cocaine that lead to its abuse. Because several of the compounds under study bind to the dopamine transporter but do not have cocaine-like behavioral effects, they may serve as tools for a better understanding of how the effects of cocaine are mediated by actions at the dopamine transporter.