Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
J Pharmacol Exp Ther. 2010 Apr;333(1):244-52. doi: 10.1124/jpet.109.163451. Epub 2010 Jan 6.
Although many drugs act by indirectly stimulating multiple receptors (e.g., reuptake inhibitors), relatively little is known about interactions between agonism at different receptors. This study compared the effect of serotonin (5-HT)(1A) receptor agonists with the discriminative stimulus effects of the 5-HT(2A) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in rats and rhesus monkeys. Eight rats discriminated 0.56 mg/kg i.p. DOM and responded under a fixed ratio (FR) 10 schedule of food presentation, whereas three rhesus monkeys discriminated 0.32 mg/kg s.c. DOM and responded under an FR 5 schedule of stimulus shock termination. DOM and the 5-HT(2A) receptor agonists 2,5-dimethoxy-4-n-propylthiophenethylamine (2C-T-7) and dipropyltryptamine (DPT), but not the 5-HT(1A) receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (8-OH-DPAT) and 3-chloro-4-fluorophenyl-(4-fluoro-4-([(5-methyl-6-methylaminopyridin-2-ylmethyl) amino) methyl] piperidin-1-yl) methanone (F13714), occasioned responding on the DOM-associated lever in rats and monkeys. Both 8-OH-DPAT and F13714 attenuated the discriminative stimulus effects of DOM in monkeys but not in rats; these effects of 8-OH-DPAT and F13714 were prevented by the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY 100635). DPT and 2C-T-7 enhanced the discriminative stimulus effects of DOM in rats and monkeys in an additive manner. Taken together, the results suggest that the DOM discriminative stimulus is pharmacologically similar and mediated by 5-HT(2A) receptors in rats and monkeys; however, the ability of 5-HT(1A) receptor agonists to modify the effects of DOM is markedly different between these species. These results indicate possible differences in the neurobiology of 5-HT systems that could be important for studying drugs that have multiple mechanisms of action (e.g., reuptake inhibitors that indirectly stimulate multiple receptors).
虽然许多药物通过间接刺激多种受体（例如再摄取抑制剂）起作用，但人们对不同受体激动作用之间的相互作用知之甚少。本研究比较了 5-羟色胺（5-HT）（1A）受体激动剂与 5-HT（2A）受体激动剂 1-（2,5-二甲氧基-4-甲基苯基）-2-氨基丙烷（DOM）在大鼠和恒河猴中的区分刺激作用。8 只大鼠辨别 0.56mg/kg 腹腔注射 DOM，并在固定比率（FR）10 的食物呈现方案下进行反应，而 3 只恒河猴辨别 0.32mg/kg 皮下注射 DOM，并在 FR5 的刺激终止方案下进行反应。DOM 和 5-HT（2A）受体激动剂 2,5-二甲氧基-4-正丙基噻吩乙胺（2C-T-7）和二丙基色胺（DPT），但不是 5-HT（1A）受体激动剂 8-羟基-2-（二正丙基氨基）四氢萘盐酸盐（8-OH-DPAT）和 3-氯-4-氟苯基-（4-氟-4-[[（5-甲基-6-甲基氨基吡啶-2-基）甲基]氨基]甲基）哌啶-1-基）甲酮（F13714），使大鼠和猴子在与 DOM 相关的杠杆上产生反应。8-OH-DPAT 和 F13714 均减弱了 DOM 在猴子中的区分刺激作用，但在大鼠中没有；这些 8-OH-DPAT 和 F13714 的作用被 5-HT（1A）受体拮抗剂 N-[2-[4-（2-甲氧基苯基）-1-哌嗪基]乙基]-N-（2-吡啶基）环己烷甲酰胺（WAY 100635）所阻止。DPT 和 2C-T-7 以相加的方式增强了大鼠和猴子中 DOM 的区分刺激作用。总的来说，结果表明，在大鼠和猴子中，DOM 的区分刺激在药理学上与 5-HT（2A）受体相似，并由其介导；然而，5-HT（1A）受体激动剂修饰 DOM 效应的能力在这些物种之间有显著差异。这些结果表明，5-HT 系统的神经生物学可能存在差异，这对于研究具有多种作用机制的药物（例如，间接刺激多种受体的再摄取抑制剂）可能很重要。
