A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants

  title={A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants},
  author={Sunmee Wee and F. Ivy Carroll and William L. Woolverton},
A slow onset of action has been hypothesized to weaken the reinforcing effects of drugs. The present study evaluated this hypothesis with slow-onset cocaine analogs, WIN 35428, RTI 31, and RTI 51. When cocaine or a cocaine analog was made available to rhesus monkeys (n=4 or 5) for self-administration under a progressive-ratio (PR) schedule with a 1-h time-out between injections, all the drugs functioned as positive reinforcers. The maximum number of injections was in the order of cocaine>WIN… 
Assessment of Reinforcing Effects of Benztropine Analogs and Their Effects on Cocaine Self-Administration in Rats: Comparisons with Monoamine Uptake Inhibitors
Low abuse liability of BZT analogs is supported and their potential development as medications for cocaine abuse is supported by the effects of their oral pretreatment on cocaine self-administration.
Assessment of the effects of contingent histamine injections on the reinforcing effectiveness of cocaine using behavioral economic and progressive-ratio designs
Results indicate that combining drug punisher with drug reinforcers reduces the maximum reinforcing effect of the drug reinforcer, which suggests a use for drug punishers as a deterrent to drug abuse (e.g., as mixtures with prescription medications with abuse potential).
Self-administration of drug mixtures by monkeys: combining drugs with comparable mechanisms of action
Mixtures of various proportions of two drugs with comparable mechanisms of action were additive, i.e., they did not interact, and this result will serve as the basis for comparison to studies of mixtures of drugs with various mechanisms ofaction.
The abuse-related effects of pyrrolidine-containing cathinones are related to their potency and selectivity to inhibit the dopamine transporter
These synthetic cathinones were more effective reinforcers than cocaine, and the measures of reinforcing effectiveness determined by PR and demand curve analyses were highly correlated with selectivity for DAT over SERT.
Nonclassical Pharmacology of the Dopamine Transporter: Atypical Inhibitors, Allosteric Modulators, and Partial Substrates
Compounds with conformation-specific activity are discussed, useful not only as tools for studying the mechanics of dopamine transport, but also as leads for medication development in addictive disorders.
The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors
Modafinil displayed affinity ratios similar to those of benztropine, GBR12909 and bupropion, but far different than those of cocaine, β-CFT or methylphenidate, and it was demonstrated that the conformational effects of a given DAT inhibitor influence its phenomenological effects.
Interaction of cocaine‐, benztropine‐, and GBR12909‐like compounds with wild‐type and mutant human dopamine transporters: molecular features that differentially determine antagonist‐binding properties
This study furthers the concept of using DAT mutants to differentiate cocaine‐like inhibitors from atypical inhibitors in vitro, and points to the importance of specific molecular features – most notably the presence of a diphenylmethoxy moiety – in determining a compound’s binding profile.
Self-administration of cocaine–remifentanil mixtures by monkeys: an isobolographic analysis
Combinations of cocaine and remifentanil can be additive or super-additive as positive reinforcers, depending on proportions of each.
Pharmacological determinants of the reinforcing effects of psychostimulants: relation to agonist substitution treatment.
  • J. Lile
  • Psychology, Medicine
    Experimental and clinical psychopharmacology
  • 2006
Evidence is presented to support the conclusion that affinity for dopamine transporters appears to be of critical importance, whereas serotonintransporters seem to serve a modulatory function, and that slow-onset, long-acting monoamine transporter ligands can be expected to have reinforcing effects and therefore abuse liability, which has implications for the use of these drugs as pharmacotherapies.


Rate of binding of various inhibitors at the dopamine transporter in vivo
There was no obvious correlation between rate of occupancy in this animal model and abuse liability in humans, which is consistent with the notion that other factors are critical as well.
Reinforcing Strength of a Novel Dopamine Transporter Ligand: Pharmacodynamic and Pharmacokinetic Mechanisms
The results suggest that (+)-CPCA is a weaker positive reinforcer than cocaine because it has a slower onset of action over the first few minutes after i.v. injection.
Relationship between injection duration, transporter occupancy and reinforcing strength of cocaine.
The Reinforcing Efficacy of the Dopamine Reuptake Inhibitor 2β-Propanoyl-3β-(4-tolyl)-tropane (PTT) as Measured by a Progressive-Ratio Schedule and a Choice Procedure in Rhesus Monkeys
Results suggest that the reinforcing efficacy of PTT is less than cocaine in nonhuman primates, and indicate that slow-onset, long-acting DAT inhibitors can decrease cocaine self-administration while not functioning robustly as reinforcers, and support the further investigation of these drugs as treatment for cocaine addiction.
Further studies of the reinforcing effects of benztropine analogs in rhesus monkeys
This study confirms and extends previous results suggesting that compounds with high DAT affinity can have strong, moderate, weak, or no effectiveness as reinforcers.
On the relationship between the dopamine transporter and the reinforcing effects of local anesthetics in rhesus monkeys: practical and theoretical concerns
The potency of local anesthetics as positive reinforcers is likely related to their potency as DA uptake inhibitors, which may be related to relative potency over the concentrations that are achieved in vivo.
Differential regulation of dopamine transporter after chronic self-administration of bupropion and nomifensine.
Evidence is provided for heterogeneity among DA reuptake inhibitors, with some of these drugs being able to up-regulate DA transporters after their self-administration, whereas others lack this neuroadaptive response.
Measuring dopamine transporter occupancy by cocaine in vivo: Radiotracer considerations
The hypothesis that the measurement of DAT occupancies by drugs with fast pharmacokinetics such as cocaine requires a radioligand with similar kinetics in order to effectively compete with the drug is tested.
Relationship between the Serotonergic Activity and Reinforcing Effects of a Series of Amphetamine Analogs
The results suggest that the mechanism for this effect involves a decrease in reinforcing potency and efficacy among monoamine releasing agents when 5-HT releasing potency is increased relative to DA.
Effects of route of administration on cocaine induced dopamine transporter blockade in the human brain.