Sigma receptor (σR) antagonists attenuate many behavioral effects of cocaine, but typically not its reinforcing effects in self-administration procedures. However, the σR antagonist rimcazole and its N-propylphenyl analogs, SH 3-24 and SH 3-28, dose-dependently decreased the maximal rates of cocaine self administration without affecting comparable responding maintained by food reinforcement. In contrast, a variety of σR antagonists (AC927, BD 1008, BD 1047, BD 1063, NE-100) had no effect on cocaine self-administration across the range of doses that decreased rates of food-maintained responding. Rimcazole analogs differed from selective σR antagonists in their dual affinities for σRs and the dopamine transporter (DAT) assessed with radioligand binding. Selective DAT inhibitors and σR antagonists were studied alone and in combination on cocaine self-administration to determine whether actions at both σRs and the DAT were sufficient to reproduce the effects of rimcazole analogs. Typical DAT inhibitors (WIN 35,428, methylphenidate, nomifensine) dose-dependently shifted the cocaine dose-effect curve leftward. Combinations of DAT-inhibitor and σR-antagonists doses that were behaviorally inactive alone decreased cocaine self-administration without effects on food-maintained responding. Additionally, whereas the DAT inhibitors were self-administered at rates similar to those of cocaine, neither rimcazole analogs nor typical σR antagonists (NE-100, AC927) maintained responding above control levels across a wide range of doses. These findings suggest that unique effects of rimcazole analogs are due to dual actions at the DAT and σRs, and that a combined target approach may have utility in development of medical treatments for cocaine abuse.
- Received June 13, 2011.
- Revision received August 18, 2011.
- Accepted August 19, 2011.
- The American Society for Pharmacology and Experimental Therapeutics