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

Abstract

Although inhibition of dopamine transporters (DAT) and the subsequent increase in dopamine clearly play a role in the effects of psychomotor stimulants, the reinforcing effectiveness of DAT inhibitors varies. Previous studies suggest that pharmacokinetic and pharmacodynamic properties of these drugs account for this variability. The present studies compared the time-course and behavioral effects of five phenyltropane analogs of cocaine with high affinity for DAT and varying time courses of action in rhesus monkeys. The rate of drug uptake in putamen was measured using positron emission tomography neuroimaging. The rank order of the time to peak drug uptake was cocaine < RTI-336 < RTI-150 < RTI-113 < RTI-177. Cocaine and all five analogs fully substituted for the cocaine cue in animals trained to discriminate cocaine from saline. All of the drugs were selfadministered under a progressive-ratio schedule of drug self-administration and reinstated previously extinguished self-administration maintained under a second-order schedule. The time to peak drug uptake corresponded closely with the time to peak discriminative-stimulus effects, and there was a trend for the time of peak drug uptake to correspond negatively with the peak number of drug infusions. Collectively, these results indicate that the rate of drug entry in brain can play an important role in the behavioral pharmacology of psychomotor stimulants.

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

“…Also, CTDP-32476 pretreatment dose-dependently inhibited cocaine-taking and cocaine-seeking behavior, as assessed by cocaine selfadministration under both FR2 and PR reinforcement and by a shift in the cocaine self-administration dose-response curve, suggesting that a reduction in cocaine's rewarding effects may underlie the reduction of cocaine selfadministration after CTDP-32476 administration. This action and the underlying mechanisms may be different from those produced by other DAT inhibitors such as GBR-12909, PTT, and some RTI compounds, although they also dose-dependently inhibit cocaine self-administration and attenuate cocaine intake (Glowa et al, 1996;Howell and Wilcox, 2001;Kimmel et al, 2008;Negus et al, 2009;Rothman et al, 2008;Tanda et al, 2009). The precise mechanisms underlying such actions remain unclear.…”

“…It is well-documented that cocaine's rapid onset of action contributes to its highly-rewarding efficacy and addictive potential (Busto and Sellers, 1986;Kimmel et al, 2008;Kimmel et al, 2007), although not all studies support this view (Li et al, 2011). In rodents, different rates of cocaine delivery affect its addictive liability-drugs reaching the brain rapidly are more addictive than those that reach the brain slowly (Oldendorf, 1992;Samaha and Robinson, 2005;Wakabayashi et al, 2010).…”

“…Several other ligands such as GBR-12909, PTT [2β-propanoyl-3β-(4-tolyl)-tropane], and RTI (Research Triangle Institute) compounds (3-phenyltropane analogs) have been previously thought to be 'slow-onset long-acting' DAT inhibitors (Howell and Wilcox, 2001;Rothman et al, 2008). However, in vivo microdialysis and fast-cyclic voltammetry studies suggest that they are actually fast-onset (Espana et al, 2008) and have only slightly longer durations of action than cocaine (2-3 h vs 1-2 h) with respect to enhanced extracellular nucleus accumbens (NAc) DA (Baumann et al, 1994;Budygin et al, 2000;Kimmel et al, 2008;Kimmel et al, 2007;Nakachi et al, 1995). These data suggest that such DAT inhibitors may have similar addictive potential as cocaine.…”

Nonhuman Primate Neuroimaging and Cocaine Medication Development

“…In PET neuroimaging studies which characterized the time-course of drug uptake in brain, there was a clear trend towards an inverse relationship between the time to peak uptake of [ 11 C]-labeled drugs in putamen and the peak number of infusions received under a progressive ratio schedule of i.v. self-administration, such that the faster-onset drugs produced greater levels of responding relative to the slower-onset drugs (Kimmel et al, 2008). There also was a close correspondence between the time course of drug uptake in brain and drug-induced increases in extracellular dopamine in caudate (Ginsburg et al, 2005;Kimmel et al, 2007Kimmel et al, , 2008.…”

“…The affinities of several cocaine-like drugs for the DAT correlate well with their potencies for supporting self-administration behavior (Ritz et al, 1987;Bergman, Madras, Johnson, & Spealman, 1989;Wilcox, Paul, & Woolverton, 1999). Cocaine and selective DAT inhibitors exert similar effects on schedule-controlled behavior and are reliably self-administered in squirrel monkeys (Bergman et al, 1989;Howell & Byrd, 1991;Howell, Czoty, Kuhar, & Carroll, 2000;Kimmel, O'Connor, Carroll, & Howell, 2007) and rhesus monkeys (Nader, Grant, Davies, Mach, & Childers 1997;Lile et al, 2003;Lindsey et al, 2004;Wilcox et al, 2005Kimmel et al, 2008). Importantly, a variety of preclinical studies in nonhuman primates provide evidence that DAT inhibitors can effectively attenuate cocaine self-administration (Glowa et al, 1995;Nader et al, 1997;Howell et al, 2000;Wilcox et al, 2002;Lindsey et al, 2004;.…”