The reinforcing efficacy of psychostimulants in rhesus monkeys: The role of pharmacokinetics and pharmacodynamics

This study was undertaken to investigate pharmacological variables that influence the reinforcing efficacy of psychostimulants. Rhesus monkeys (n = 9) responded under a within-session, exponentially increasing, progressive ratio schedule of cocaine reinforcement. Doses of cocaine, methylphenidate (MP), cocaine analogs [(±)-2β-propanoyl-3β-(2-naphthyl)-tropane (WF-23), HD-23; (±)-2β-propanoyl-3β-(2-isopropenyl)-tropane (WF-60), HD-60; and 2β-propanoyl-3β-(4-tolyl)-tropane (HD-11, WF-11), and 2β-propanoyl-3β-(4-tolyl)-tropane (HD-11, WF-11), PTT], and MP analogs [(αR,2R)-α-(2-naphthalenyl)-2-piperidineacetic acid methyl ester, HDMP-28; and (αR,2S)-α-(2-naphthalenyl)-2-pyrrolideneacetic acid methyl ester, HDMP-29] that varied in their pharmacokinetic and pharmacodynamic properties were substituted for cocaine. These drugs were chosen according to their selectivity for dopamine transporters (DAT) and 5-hydroxytryptamine (serotonin) transporters (5-HTT) as assessed in rodents and their duration of action. In addition, data pertaining to the rate of onset at DAT were collected for the cocaine analogs using an ex vivo binding assay in rodent tissue. Finally, the pharmacodynamic profile of select drugs was confirmed in primate brain tissue. All drugs had reinforcing effects except HDMP-29. The rank ordering of the peak breaking points (BPs) was cocaine = MP = HDMP-28 ≥ HD-60 ≥ PTT ≥ HD-23 > HDMP-29. The time to peak DAT occupancy for the cocaine analogs was greater than 30 min. The potency to maintain peak BP was significantly correlated with DAT affinity. 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. Interestingly, the 5-HTT-selective cocaine analog HD-60 functioned robustly as a reinforcer at several doses in all monkeys tested. These data question the dogma regarding the role of pharmacokinetic factors and the relative influence of DAT and 5-HTT in stimulant reinforcement.