Department of Psychological Sciences, University of Missouri, Columbia, MO 65211, USA.
Pharmacol Biochem Behav. 2011 Feb;97(4):676-82. doi: 10.1016/j.pbb.2010.11.016. Epub 2010 Nov 27.
Cocaine exhibits preferential (~15-fold) affinity for σ₁ over σ₂ sigma receptors, and previous research has shown an interaction of σ₁ receptor-selective ligands and cocaine's behavioral effects. The present study investigated the effect of the putative sigma receptor agonist SA 4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride) on cocaine's locomotor stimulatory and discriminative stimulus properties. At doses without intrinsic activity, SA 4503 dose-dependently attenuated cocaine-induced hyperactivity in mice. This inhibition was overcome by increasing the cocaine dose. In rats trained to use cocaine as a discriminative stimulus in a drug discrimination task, doses of SA 4503 that did not substitute for the cocaine stimulus did not alter the cocaine substitution curve. However, SA 4503 potentiated the effect of methamphetamine to substitute for the cocaine stimulus. These data support a role for sigma receptors in the locomotor-activating properties of cocaine and, importantly, indicate a role for these receptors in the discriminative stimulus effects of methamphetamine. The data also suggest sigma receptors mediate the activity of different dopamine pathways responsible for the behavioral effects of psychostimulants.
可卡因对 σ₁ 比 σ₂ 型 sigma 受体具有优先 (~15 倍) 的亲和力,先前的研究表明 σ₁ 受体选择性配体与可卡因的行为效应相互作用。本研究调查了假定的 sigma 受体激动剂 SA 4503(1-(3,4-二甲氧基苯乙基)-4-(3-苯基丙基)哌嗪二盐酸盐)对可卡因的运动兴奋和辨别刺激特性的影响。在没有内在活性的剂量下,SA 4503 剂量依赖性地减弱了可卡因诱导的小鼠多动。通过增加可卡因剂量可以克服这种抑制。在接受可卡因作为药物辨别任务中的辨别刺激的大鼠中,不替代可卡因刺激的 SA 4503 剂量并未改变可卡因替代曲线。然而,SA 4503 增强了 methamphetamine 替代可卡因刺激的作用。这些数据支持 sigma 受体在可卡因的运动激活特性中的作用,重要的是,表明这些受体在 methamphetamine 的辨别刺激效应中的作用。数据还表明,sigma 受体介导负责精神兴奋剂行为效应的不同多巴胺途径的活性。