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

Abstract

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 ¼ 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 cocaine4WIN 354284RTI 314RTI 51. In in vivo binding in rat striatum, equipotent doses of cocaine, WIN 35428, RTI 31, and RTI 51 were estimated to displace 25% of [ 3 H]WIN 35428 binding at the dopamine transporters (DAT), respectively, 5.8, 22.4, 30.8, and 44.1 min after the intravenous injection. Further, relative reinforcing efficacy was correlated with rate of DAT binding such that slower displacement of [ 3 H]WIN 35428 was associated with a weaker reinforcing effect. In in vitro binding in monkey brain tissue, the cocaine analogs had higher affinity for monoamine transporter sites, but similar affinity ratios of 5-HTT/DAT, compared to cocaine. Lastly, RTI 31 was shown to function as a positive reinforcer in drug-naïve rhesus monkeys under a fixed-ratio 1 schedule. Collectively, the data support the hypothesis that a slow onset at the DAT is associated with reduced reinforcing efficacy of DAT ligands. The data under both the PR and FR schedules, however, suggest that a slow onset at the DAT influence reinforcing effect only to a limited extent.

Assessment of Reinforcing Effects of Benztropine Analogs and Their Effects on Cocaine Self-Administration in Rats: Comparisons with Monoamine Uptake Inhibitors

“…Lile et al (2000) suggested that the impact of uptake and distribution on binding association kinetics is a critical factor in reinforcing effectiveness of DAT inhibitors. In their study, 2␤-propanoyl-3␤-(4-tolyl)-tropane, a DAT inhibitor with reduced reinforcing effectiveness in primates, had a lower apparent DAT association rate compared with cocaine in rats, presumably because of slower uptake and distribution (see also Wee et al, 2006;Kimmel et al, 2008). However, as also noted (Woolverton et al, 2002;, actions at other sites may obscure relationships between reinforcing effectiveness and rate of DAT occupancy.…”

Nonclassical Pharmacology of the Dopamine Transporter: Atypical Inhibitors, Allosteric Modulators, and Partial Substrates

“…One factor thought to impact the rewarding efficacy of a given psychostimulant is the rate at which the compound enters the brain and interacts with the DAT; compounds with a rapid onset of action tend to exhibit greater addictive potential than do those with a slower onset rate (Wee et al, 2006). Even cocaine was found to have lower reinforcing efficacy in a primate progressive-ratio selfadministration paradigm when injected over a period of 10 minutes, as opposed to a period of 10 seconds (Woolverton and Wang, 2004).…”

Self-administration of cocaine–remifentanil mixtures by monkeys: an isobolographic analysis

“…Monkey 96R0679 had a history of self-administration of the phenyltropane RTI-31 under a fixed-ratio 1 (FR1) schedule of reinforcement (Wee et al 2006). Monkeys RiK2, R0697, M1338, and R0463 had self-administered a variety of compounds under PR schedules similar to the one used here (Woolverton et al 2008).…”