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

Abstract

Rationale: The discriminative-stimulus effects of cocaine have been reported to be mediated by indirect agonist actions initiated by the blockade of dopamine uptake, and the potencies of drugs that have discriminativestimulus effects like cocaine are directly related to their dopamine transporter binding affinities. The binding to the dopamine transporter by cocaine and many of its analogs has been reported to fit better using a two-site model than a one-site model. Objectives: The present study examined the relationship among binding affinities of dopamine uptake inhibitors at these two sites and their potencies to produce discriminative-stimulus effects. Methods: The inhibition constants (K i values) were derived for unlabeled dopamine uptake inhibitors for displacement of [ 3 H]WIN 35,428 from rat caudate putamen membranes. These K i values were related to the ED 50 values obtained in rats 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 35,428, nomifensine, WIN 35,981, WIN 35,065-2, methylphenidate, cocaine, cocaethylene, and bupropion) were better fit by a two-site model than a one-site model. 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 the high-affinity site and the ED 50 values (R 2 =0.655; P=0.015) than there was for the low-affinity site (R 2 =0.543; P=0.037). Of the remaining drugs, there was a high correlation among the K i values and the ED 50 values for the discriminative-stimulus effects (R 2 =0.523; P=0.012). Conclusions: These data suggest that the discriminative-stimulus effects of cocaine are more closely related to actions mediated by high-affinity binding to the dopamine transporter than they are to actions mediated by the low-affinity site. The further assessment of the respective contributions of high-and lowaffinity binding to the behavioral effects of cocaine will be greatly enhanced with the development of pharmacological tools that have a high degree of selectivity for one of these components.

Interactions of Cocaine with Dopamine Uptake Inhibitors or Dopamine Releasers in Rats Discriminating Cocaine

“…We replicated previous findings that the present DA uptake inhibitors (e.g., Broadbent et al, 1991;Baker et al, 1993;Kleven et al, 1999;Katz et al, 2000) and DA releasers substitute completely for cocaine (e.g., D'Mello and Stolerman, 1977;Risner et al, 1985;Wood and EmmettOglesby 1988;Ukai et al, 1993;Young and Glennon, 1993;Koetzner et al, 1996). When DA uptake inhibitors and DA releasers were given before or concurrently with cocaine, the cocaine dose-effect function was shifted to the left, with a trend toward a change in the slope of the dose-effect curve.…”

Influence of Naturally Occurring Variations in Maternal Care on Prepulse Inhibition of Acoustic Startle and the Medial Prefrontal Cortical Dopamine Response to Stress in Adult Rats

“…, a specific DAT ligand (K d of 0.9 nM for the high-affinity DA uptake site) (Vignon et al, 1988;Katz et al, 2000). Nonspecific binding was determined from two adjacent sections by adding 1 M GBR12935 to the binding buffer.…”

Methylphenidate Restores Ventral Tegmental Area Dopamine Neuron Activity in Prenatal Ethanol-Exposed Rats by Augmenting Dopamine Neurotransmission

“…Nomifensine and GBR 12909 are specific DA reuptake blockers and yet their effect is more similar to amphetamine than to methylphenidate. Therefore, the differences in the effect of amphetamine and methylphenidate on DA neuron activity could be due to other factors dictating the in vivo effects of these drugs (e.g., differences in bioavailability, brain pharmacokinetics, binding to different sites, potency to block the dopamine transporter; Katz et al, 2000). Interestingly, some investigators have reported that nomifensine has the properties of a DA releaser (Hurd and Ungerstedt, 1989) and weak DA receptor agonist (Gianutsos et al, 1982) in addition to pure transporter blocker (e.g., methylphenidate).…”