Relationships among dopamine transporter affinities and cocaine-like discriminative-stimulus effects

Rationale: The discriminative-stimulus effects of cocaine have been reporte d to be mediated by indirect agonist actions initiated by the blockade of d opamine uptake, and the potencies of drugs that have discriminative-stimulu s effects like cocaine an directly related to their dopamine transporter bi nding affinities. The binding to the dopamine transporter by cocaine and ma ny of its analogs has been reported to fit better using a two-site model th an a one-site model. Objectives: The present study examined the relationshi p among binding affinities of dopamine uptake inhibitors at these two sites and their potencies to produce discriminative-stimulus effects. Methods: T he inhibition constants (K-i values) were derived for unlabeled dopamine up take inhibitors for displacement of [H-3]WIN 35,428 from rat caudate putame n membranes. These K-i values were related to the ED50 values obtained in r ats trained to discriminate 10 mg/kg cocaine from saline injections under a fixed-ratio 20 schedule of food reinforcement. Results: Among the dopamine uptake inhibitors studied, the binding data for eight compounds (WIN 35,42 8, nomifensine, WIN 35,981, WIN 35,065-2, methylphenidate, cocaine, cocaeth ylene, and bupropion) were better fit by a two-site model than a one-site m odel. The data for the remaining eleven compounds (RTI-31, RTI-55, RTI-121, RTI-32, LU19-005, BTCP, GBR12909, GBR12935, mazindol, LU17-133, and EXP561 ) were better fit by a one-site model. Of the drugs that were fit best by a two-site model, there was a higher correlation among the K-i values for th e high-affinity site and the ED50 values (R-2=0.655; P=0.015) than there wa s for the low-affinity site (R-2=0.543; P=0.037). Of the remaining drugs, t here was a high correlation among the K-i values and the ED50 values for th e discriminative-stimulus effects (R-2=0.523; P=0.012). Conclusions: These data suggest that the discriminative-stimulus effects of cocaine are more c losely related to actions mediated by high-affinity binding to the dopamine transporter than they are to actions mediated by the low-affinity site. Th e further assessment of the respective contributions of high- and low-affin ity binding to the behavioral effects of cocaine will be greatly enhanced w ith the development of pharmacological tools that have a high degree of sel ectivity for one of these components.