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

Abstract

This study was undertaken to investigate pharmacological variables that influence the reinforcing efficacy of psychostimulants. Rhesus monkeys (n ϭ 9) responded under a withinsession, exponentially increasing, progressive ratio schedule of cocaine reinforcement. Doses of cocaine, methylphenidate (MP), cocaine analogs [(Ϯ)-2␤-propanoyl-3␤-(2-naphthyl)-tropane (WF-23), HD-23; (Ϯ)-2␤-propanoyl-3␤-(2-isopropenyl)-tropane (WF-60), HD-60; and 2␤-propanoyl-3␤-(4-tolyl)-tropane (HD-11, WF-11), and 2␤-propanoyl-3␤-(4-tolyl)-tropane (HD-11, WF-11), PTT], and MP analogs [(␣R,2R)-␣-(2-naphthalenyl)-2-piperidineacetic acid methyl ester, HDMP-28; and (␣R,2S)-␣-(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 ϭ MP ϭ HDMP-28 Ն HD-60 Ն PTT Ն HD-23 Ͼ 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.Although the use of psychomotor stimulants such as cocaine and various amphetamine derivatives has remained stable over the past several years (SAMHSA, 2001), an effective pharmacotherapy has yet to be developed. An understanding of the pharmacological properties that mediate the abuse liability of these drugs will assist in the design of treatments for psychostimulant abuse and dependence and result in a better understanding of addiction. Animal models of drug self-administration have allowed for the systematic investigation of drug-reinforced behavior; however, the variables that influence the reinforcing efficacy of psychostimulants are still not fully understood.One pharmacological attribute common to psychostimu-

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

“…Similarly, a piperidine cocaine analog, which has slightly weaker affinity at the DAT than cocaine, was a weaker reinforcer than cocaine . However, when a correlation between efficacy as a reinforcer and potency at the DAT was made among seven monoamine transporter inhibitors, no relationship was found (Lile et al, 2003). Interestingly, the present study found a negative relationship between binding affinities at the DAT in vivo and reinforcing efficacy and between binding affinities at the DAT in vitro and reinforcing efficacy.…”

“…In two-drug comparisons, diminished reinforcing efficacy of a piperidine analog or a tropane analog (Lile et al, 2002) relative to cocaine was attributed to its slower rate of onset. On the other hand, in a comparison across several drugs, no obvious relationship between rate of onset and reinforcing efficacy was observed (Lile et al, 2003). Therefore, the relationship between onset of action and reinforcing efficacy across DAT ligands remains equivocal.…”

Estimating the relative reinforcing strength of (±)-3,4-methylenedioxymethamphetamine (MDMA) and its isomers in rhesus monkeys: comparison to (+)-methamphetamine

“…Although the present results lend support, the conclusion that increased 5-HT actions relative to DA can decrease reinforcing strength, it should be pointed out that Lile et al (2003) reported self-administration by monkeys of a cocaine analog and DA uptake blocker, HD-60, with at least 80-fold selectivity for SERT relative to the DAT binding. Other compounds tested in monkeys that support the DA/5-HT hypothesis have been primarily monoamine releasers (Ritz and Kuhar 1989;Wee et al 2005), raising the possibility that there is a difference between monoamine release and reuptake blockade in terms of reinforcing effects.…”

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

“…When cocaine was infused more slowly, it was found to be less effective as a reinforcer in nonhuman primates (Balster and Schuster, 1973;Panlilio et al, 1998). 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).…”

“…A recent review suggests that a rapid onset of action is associated with the reinforcing effects of a drug but is not required for a drug to act as a reinforcer (Lile, 2006). Similarly, several other phenylpiperazine and phenyltropane DAT inhibitors function as positive reinforcers in nonhuman primates despite a slow onset of DAT binding Lile et al, 2003;Spealman and Kelleher, 1981). Indeed, decreasing the rate of cocaine infusion in rhesus monkeys decreased the reinforcing strength of the drug, but only to a certain point, suggesting a "floor" effect in the absence of alternate reinforcers (Woolverton and Wang, 2004).…”