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

Abstract

Although the behavioral-stimulant and reinforcing effects of cocaine and related psychomotor stimulants have been attributed to their actions at the dopamine transporter (DAT), the reinforcing effectiveness of these compounds varies. The properties that confer these differences are important considerations when developing agonist pharmacotherapies for the treatment of stimulant abuse. The present studies focused on the time course of action and pharmacological specificity of six 3-phenyltropane analogs of cocaine (RTI-112, RTI-126, RTI-150, RTI-171, RTI-177, and RTI-336) by observing their behavioral-stimulant, neurochemical, and reinforcing effects in squirrel monkeys. The faster-onset analogs (RTI-126, RTI-150, and RTI-336), and one of the slower-onset DAT selective analogs (RTI-177 and RTI-171) produced behavioral-stimulant effects, while the sloweronset nonselective analog RTI-112 did not. The time to the peak behavioral-stimulant effect and the peak caudate dopamine levels was strongly correlated, but the area under the curve of the time course of behavioral-stimulant effect and dopamine levels was not correlated. These results suggest that the rate of onset plays a more important role than duration of action in the stimulant effect of these analogs. In addition, the slower-onset nonselective analog (RTI-112) clearly did not exhibit any reinforcing effects while the faster-onset nonselective (RTI-126) and all the DAT-selective analogs showed robust reinforcing effects (RTI-150, and RTI-177) or showed trends towards reinforcing effects (RTI-336 and RTI-171). Hence, there was a general trend for compounds that had a faster onset and/or DAT selectivity to produce significant behavioral-stimulant and reinforcing effects.

Increased vulnerability to cocaine in mice lacking dopamine D3receptors

“…We define the NAc DA response to cocaine as cocaine-induced changes in DA over baseline (i.e., percent of baseline). This is important because the rate of change in extracellular DA is positively correlated with a drug's rewarding efficacy and addictive potential; the faster the increase in extracellular DA, the higher the drug-induced reward and the psychomotor stimulation (32)(33)(34). In light of this, reduced DA elevation to cocaine suggests reduced cocaine reward in D 3 −/− mice.…”

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

“…All drug doses were determined as salts. The five phenyltropane analogs of cocaine were selected based on their high affinity for the DAT and varying time courses of action Kimmel et al, 2001;Kimmel et al, 2007;Kuhar et al, 1999) (Table 1).…”

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

“…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.…”