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 slower-onset 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.

Figure 1

Dose-response curve of stimulant effects of nonselective monoamine transporter inhibitors (A, B) and selective DAT inhibitors (C–F) on responding maintained by an FI schedule in squirrel monkeys (n=3). Data points represent mean ± SEM rate of responding averaged across the 13-component session. Asterisks (*) represent individual points significantly different from saline control, based on Tukey’s post-hoc multiple comparisons tests.

Figure 2

Time course of stimulant effects of nonselective monoamine transporter inhibitors (A, B) and selective DAT inhibitors (C–F) on responding maintained by an FI schedule in squirrel monkeys (n=3). Data points represent mean ± SEM rate of responding in each of 13 consecutive 5-min intervals. A 1-min timeout separated each 5-min FI component.

Figure 3

Effects of nonselective monoamine transporter inhibitors (A, B) and selective DAT inhibitors (C–F) on extracellular dopamine in the caudate nucleus of unanesthetized squirrel monkeys as determined with in vivo microdialysis (n=3). Drugs were administered i.m. at time point zero. Data points represent mean ± SEM dopamine levels as a percent of values obtained prior to drug administration.

Figure 4

Correlations between the time to peak (A) and the area under the curve (B) of behavioral-stimulant effects and dopamine levels of each compound.

Figure 5

Effects of nonselective monoamine transporter inhibitors (A, B) and selective DAT inhibitors (C–F) on responding maintained by a second-order schedule of cocaine self-administration in squirrel monkeys (n=3). Data points represent mean ± SEM rate of responding. The dashed line represents responding maintained by 0.1 mg/inf of cocaine. Asterisks (*) represent individual points significantly different from saline control and crosses (+) represent individual points significantly different from cocaine, based on Tukey’s post-hoc multiple comparisons tests.