Reinforcing Strength of a Novel Dopamine Transporter Ligand: Pharmacodynamic and Pharmacokinetic Mechanisms

Abstract

Drugs that block dopamine uptake often function as positive reinforcers but can differ along the dimension of strength or effectiveness as a positive reinforcer. The present study was designed to examine pharmacological mechanisms that might contribute to differences in reinforcing strength between the piperidine-based cocaine analog (ϩ)-methyl 4␤-(4-chlorophenyl)-1-methylpiperidine-3-␣-carboxylate [(ϩ)-CPCA] and cocaine. Drugs were made available to rhesus monkeys (n ϭ 5) for i.v. self-administration under a progressive ratio schedule. Both compounds maintained responding with sigmoidal or biphasic dose-response functions (0.1-1.0 mg/kg/injection). (ϩ)-CPCA was one-fourth as potent as cocaine and maintained fewer injections per session, at maximum. For in vitro binding in monkey brain tissue, (ϩ)-CPCA was about one-half as potent as cocaine at the dopamine transporter (DAT), and the two compounds had similar affinities at the norepinephrine transporter. (ϩ)-CPCA was less than 1/10 as potent as cocaine at the serotonin transporter. In ex vivo binding in rat striatum, occupancy of the DAT increased directly with dose to a maximum of approximately 80% for both compounds, and (ϩ)-CPCA was about one-fourth as potent as cocaine. Ex vivo DAT occupancy was significantly higher for cocaine than (ϩ)-CPCA at 2 min after injection but similar at other times. Thus, the primary differences between these compounds were in serotonin transporter affinity and the kinetics of DAT binding. These results suggest that (ϩ)-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.

Evaluation of the Reinforcing Effects of Monoamine Reuptake Inhibitors Under a Concurrent Schedule of Food and I.V. Drug Delivery in Rhesus Monkeys

“…drug availability (Balster and Schuster, 1973;Griffiths et al, 1978;Risner and Jones 1976;Bergman et al, 1989). In this regard, double alternation schedules like the one used in the present study previously have been used only in single-lever self-administration studies (Woolverton et al, 2001(Woolverton et al, , 2002. It is noteworthy that functions describing the relation between response allocation and unit dose of drug obtained on the first and second days of the double alternation schedule were comparable and, also, were similar to previously reported effects of these drugs under different choice procedures (Iglauer and Woods, 1974;Paronis et al, 2002;Negus, 2003).…”

Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys

“…Similarly, the cocaine analog HD-23, which takes 60 min to attain significant binding was not as reinforcing in rhesus monkeys as were cocaine or methylphenidate (Lile et al, 2003). The piperazine analog (+)-CPCA binds to DAT more slowly than cocaine and was found to be a less robust reinforcer than cocaine in nonhuman primates (Woolverton et al, 2002). Woolverton et al (2002) have suggested that reinforcing strength may be related to the rate of DAT occupancy over a time frame within 3 min after injection.…”

“…The piperazine analog (+)-CPCA binds to DAT more slowly than cocaine and was found to be a less robust reinforcer than cocaine in nonhuman primates (Woolverton et al, 2002). Woolverton et al (2002) have suggested that reinforcing strength may be related to the rate of DAT occupancy over a time frame within 3 min after injection. The rate of drug onset also plays a role in determining its behavioral-stimulant effects, as evidenced by the strong correlation between the time to peak dopamine levels and peak behavioral-stimulant effects in the present study.…”

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

“…The method for in vivo binding studies has been described previously (Stathis et al, 1995;Woolverton et al, 2002).…”

“…In dose-response functions, the ratio data were transformed to the percentage of saline data and analyzed using nonlinear regression analysis assuming a one-site interaction (Prism 3.0, GraphPad, San Diego, CA The time point for 25% of the DAT binding was used because cocaine showed 25% of the displacement of the radioligand binding 2 min after the i.v. injection, a time that appears particularly relevant to the reinforcing effect (Volkow et al, 2000;Woolverton et al, 2002). The time point of 50% of the DAT binding was chosen because it was the maximum binding achieved by an ED 50 dose.…”