Psychobiology Section, Medications Discovery Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 251 Bayview Blvd., Suite 200, Baltimore, MD 21224, USA.
J Pharmacol Exp Ther. 2011 Nov;339(2):662-77. doi: 10.1124/jpet.111.185025. Epub 2011 Aug 22.
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, [3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]diphenylamine hydrochloride (SH 3-24) and 9-[3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide (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 [N-phenethylpiperidine oxalate (AC927), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine dihydrobromide (BD 1047), N-[2-(3,4-dichlorophenyl) ethyl]-4-methylpiperazine dihydrochloride (BD 1063), and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (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 [2β-carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428), methylphenidate, and nomifensine] dose-dependently shifted the cocaine dose-effect curve leftward. Combinations of DAT inhibitor and σR antagonist doses that were behaviorally inactive alone decreased cocaine self-administration without effects on food-maintained responding. In addition, whereas the DAT inhibitors were self-administered at rates similar to those of cocaine, neither rimcazole analogs nor typical σR antagonists (NE-100 and AC927) maintained responding above control levels across a wide range of doses. These findings suggest that the 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.
sigma 受体（σR）拮抗剂可减弱可卡因的许多行为效应，但通常不能减弱其在自我给药程序中的强化效应。然而，sigma 受体拮抗剂 rimcazole 及其 N-丙基苯基类似物，[3-(顺式-3,5-二甲基-4-[3-苯丙基]-1-哌嗪基）丙基]二苯甲胺盐酸盐（SH 3-24）和 9-[3-(顺式-3,5-二甲基-4-[3-苯丙基]-1-哌嗪基）丙基]咔唑氢溴酸盐（SH 3-28），剂量依赖性地降低了可卡因自我给药的最大速度，而不影响食物强化维持的可比反应。相比之下，各种 sigma 受体拮抗剂[N-苯乙基哌啶草酸盐（AC927）、N-[2-(3,4-二氯苯基）乙基]-N-甲基-2-(1-吡咯烷基）乙基胺二氢溴酸盐（BD 1008）、N-[2-(3,4-二氯苯基）乙基]-N-甲基-2-(二甲基氨基）乙基胺二氢溴酸盐（BD 1047）、N-[2-(3,4-二氯苯基）乙基]-4-甲基哌嗪二盐酸盐（BD 1063）和 N,N-二丙基-2-[4-甲氧基-3-(2-苯乙基氧基）苯基]-乙基胺单盐酸盐（NE-100）]在降低食物维持反应的剂量范围内对可卡因自我给药没有影响。Rimcazole 类似物与选择性 sigma 受体拮抗剂在 sigmaR 和多巴胺转运体（DAT）的双重亲和力上存在差异，这是通过放射性配体结合来评估的。单独研究和组合研究选择性 DAT 抑制剂和 sigma 受体拮抗剂对可卡因自我给药的影响，以确定作用于 sigmaR 和 DAT 是否足以复制 rimcazole 类似物的作用。典型的 DAT 抑制剂[2β-羧甲氧基-3β-(4-氟苯基）托烷（WIN 35,428）、哌甲酯和诺米芬新]剂量依赖性地使可卡因剂量-效应曲线向左移动。单独行为无活性的 DAT 抑制剂和 sigma 受体拮抗剂组合剂量降低了可卡因自我给药，而对食物维持反应没有影响。此外，虽然 DAT 抑制剂的自我给药速度与可卡因相似，但 rimcazole 类似物和典型的 sigma 受体拮抗剂（NE-100 和 AC927）都没有在广泛的剂量范围内将反应维持在对照水平以上。这些发现表明，rimcazole 类似物的独特作用是由于其在 DAT 和 sigmaR 上的双重作用，而联合靶标方法可能对可卡因滥用的医学治疗的发展具有实用价值。
