It has been demonstrated that σ receptor (σR) antagonists attenuate many of the behavioral effects of cocaine but typically not its reinforcing effects in self-administration procedures. Hiranita et al. investigated the effects of the σR antagonist rimcazole on cocaine reinforcement because of its unique property of also possessing significant dopamine transporter (DAT) binding activity. Rimcazole and two of its N-propylphenyl analogs at doses that did not affect comparable food-reinforced responding, dose-dependently decreased rates of cocaine self-administration. Because rimcazole analogs differ from σR antagonists in their additional affinity for the DAT, the present study assessed the relative contributions of these two activities on cocaine self-administration. σR antagonists alone had no effect on cocaine self-administration even at doses that decreased rates of food-reinforced responding. DAT inhibitors alone dose-dependently shifted the cocaine dose-effect curve to the left; however, the combination of these two activities at doses that were behaviorally inactive decreased cocaine self-administration without effects on food-maintained responses. These studies suggest that dual inhibition of DAT and σRs can more than adequately blunt the abuse liability and further suggest that actions at both sites substantially and selectively block the reinforcing effect of cocaine.
See article at J Pharmacol Exp Ther 2011, 339:662–677
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