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

  title={The Reinforcing Efficacy of the Dopamine Reuptake Inhibitor 2$\beta$-Propanoyl-3$\beta$-(4-tolyl)-tropane (PTT) as Measured by a Progressive-Ratio Schedule and a Choice Procedure in Rhesus Monkeys},
  author={Joshua A Lile and Drake Morgan and Anne M. Birmingham and Zhixia Wang and William L. Woolverton and Huw M. L. Davies and Michael A. Nader},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  pages={640 - 648}
  • J. Lile, D. Morgan, M. Nader
  • Published 1 November 2002
  • Biology, Psychology
  • Journal of Pharmacology and Experimental Therapeutics
The present series of experiments was undertaken to investigate the variables that influence the reinforcing efficacy of psychostimulants. The time of onset for dopamine transporter (DAT) occupancy of the long-acting, high-affinity DAT blocker 2β-propanoyl-3β-(4-tolyl)-tropane (PTT) was measured using an ex vivo binding assay in rodents and was determined to be significantly longer than for cocaine (30 min versus 2 min). To assess the reinforcing efficacy of PTT relative to cocaine, a discrete… 

Figures and Tables from this paper

Effects of the dopamine reuptake inhibitor PTT on reinstatement and on food- and cocaine-maintained responding in rhesus monkeys

The results suggest that PTT would decrease cocaine use, but only at doses that disrupted other behaviors, and it appears that the potency of this class of drugs to reinstate cocaine-seeking is substantially greater than their potency at decreasing cocaine self-administration.

The Reinforcing Efficacy of Psychostimulants in Rhesus Monkeys: The Role of Pharmacokinetics and Pharmacodynamics

There was not a linear relationship between monoamine transporter affinity and reinforcing efficacy, but it appeared that in nonhuman primates there is a range of DAT affinity under which maximal responding is maintained, and the 5-HTT-selective cocaine analog HD-60 functioned robustly as a reinforcer at several doses in all monkeys tested.

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

The hypothesis that a slow onset at the DAT is associated with reduced reinforcing efficacy of DAT ligands is supported and RTI 31 was shown to function as a positive reinforcer in drug-naïve rhesus monkeys under a fixed-ratio 1 schedule.

Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys

Evaluation of the Reinforcing Effect of Quetiapine, Alone and in Combination with Cocaine, in Rhesus Monkeys

There was evidence of enhancement of the reinforcing potency of cocaine, and the use of quetiapine in cocaine-addicted patients should be monitored.

Effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a progressive-ratio schedule in rhesus monkeys

These results are consistent with the hypothesis that chronic treatment with d-amphetamine decreases cocaine self-administration in rhesus monkeys, possibly by attenuating the reinforcing effects of cocaine.

Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse

The discovery and preclinical development of selective dopamine reuptake inhibitors as potential pharmacotherapies for treating cocaine addiction are presented and 3β-(4-chlorophenyl)-2β-[3-(4'-methylphenyl)isoxazol-5-yl]tropane (RTI-336) has been selected forPreclinical development.

The relative reinforcing strength of methamphetamine and D-amphetamine in monkeys self-administering cocaine

Although differences in availability and other social factors likely impact relative rates of abuse, the present data suggest that the greater reinforcing strength of methamphetamine contributes to its increased use compared with D-amphetamine.



Further evaluation of the reinforcing effects of the novel cocaine analog 2β-propanoyl-3β-(4-tolyl)-tropane (PTT) in rhesus monkeys

It is suggested that for long-acting compounds like PTT, reinforcing effects are more likely to be observed when the drug is available under a ratio-based schedule, compared to an interval- based schedule.

The reinforcing and discriminative stimulus effects of the novel cocaine analog 2beta-propanoyl-3beta-(4-tolyl)-tropane in rhesus monkeys.

It is demonstrated that the long-acting indirect dopamine agonist PTT was effective in decreasing cocaine self-administration and in abuse liability testing showed a unique behavioral profile, not functioning as a reinforcer when substituted for cocaine and producing discriminative stimulus effects similar to cocaine.

Self-administration of two long-acting monoamine transport blockers in rhesus monkeys

The results indicate that the reinforcing effects of PTT were slightly modified by a brief history of cocaine reinforcement, and that the weak reinforcing effects were most apparent when the drug was available under unlimited-access conditions.

Comparison of a novel tropane analog of cocaine, 2 beta-propanoyl-3 beta-(4-tolyl) tropane with cocaine HCl in rats: nucleus accumbens extracellular dopamine concentration and motor activity.

Comparing the quantitative and temporal effects of PTT and cocaine on in vivo neurochemical measures and motor behavior shows similar in vivo potencies for PTT on nucleus accumbens [DA]e and locomotor activity, however, these data do not support the hypothesis that the time course of increased nucleus accumens [ DA]E and stimulated locomotorActivity are related.

Behavioral and local cerebral metabolic effects of the novel tropane analog, 2 beta-propanoyl-3 beta-(4-tolyl)-tropane.

The present data demonstrate that PTT acts as a stimulant in vivo, paralleling its effects in vitro, but its behavioral and cerebral metabolic effects are qualitatively different from those of cocaine.

Self-administration of the high-affinity cocaine analog 2β-carbomethoxy-3β-(4-fluorophenyl)tropane

Reinforcing and discriminative stimulus effects of β-CIT in rhesus monkeys

Effects of cocaine and related drugs in nonhuman primates. III. Self-administration by squirrel monkeys.

The results in conjunction with those of previous studies in squirrel monkeys reveal a close correspondence between the relative potencies of cocaine and related drugs for maintaining i.v. self-administration and for increasing rates of schedule-controlled responding, suggesting that the reinforcing and psychomotor-stimulant effects of the drugs are mediated similarly.

Self-administration of cocaine analogs by rats

The data suggest that drugs with a higher affinity for the DA versus the 5-HT transporter are more likely to be self-administered than those with a lower affinity.

Evaluation of the role of norepinephrine in the reinforcing effects of psychomotor stimulants in rhesus monkeys

  • W. Woolverton
  • Biology, Psychology
    Pharmacology Biochemistry and Behavior
  • 1987