The euphorogenic and addictive properties of cocaine are believed to derive from the drug's blockade of the dopamine (DA) transporter (or reuptake site), which causes elevated synaptic levels of DA. Thus, the DA transporter may be viewed as the brain's 'cocaine receptor'. High affinity radiotracers for the DA transporter have recently been developed and can safely provide quantitative measurements of the density of this target site in the living human brain. Using cost effective SPECT (single photon emission computed tomographic) methodologies, we have evaluated [123I]Beta-CIT ((1R)-2Beta-carbomethoxy-3Beta-(4- iodophenyl)tropane) in human and nonhuman primate brain. Consistent with the known distribution of the DA transporter, striatum has the greatest number of sites, and pharmacological displacement studies in nonhuman primates have demonstrated that striatal uptake represents binding to the DA transporter. Studies with tracer doses of [123I]Beta-CIT in human subjects have shown that it has no noticeable subjective effects, no toxicological effects on blood chemistry values, and can be administered in doses within radiation exposure guidelines for research studies. In a manner analogous to our pharmacological studies in nonhuman primates, we propose to displace tracer amounts of striatal [123I]Beta-CIT with pharmacological doses of i.v. cocaine. This protocol (cocaine pharmacological challenge performed in conjunction with SPECT [123I]Beta- CIT imaging) will be performed before and during treatment with potential therapeutic agents (e.g., mazindol) which occupy the DA transporter and may block the euphorogenic effects of cocaine. The purposes of these studies are to measure the percentage of DA transporters occupies by euphorogenic doses of cocaine and to determine whether adequate percentage of DA transporters are occupied by potential pharmacotherapies which act at this site.