Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
Psychopharmacology (Berl). 2011 Feb;213(2-3):489-97. doi: 10.1007/s00213-010-2136-9. Epub 2010 Dec 21.
Indirect-acting serotonin (5-HT) receptor agonists (e.g., selective 5-HT reuptake inhibitors [SSRI]) stimulate multiple 5-HT receptors, although the role of particular receptors as well as interaction(s) among different receptors in the therapeutic effects of SSRIs is not fully understood.
Relatively few studies have systematically examined direct-acting agonists in combination. This study examined the 5-HT(1A) receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (8-OH-DPAT; 0.01-10.0 mg/kg) and 3-chloro-4-fluorophenyl-4-fluoro-4-([(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl)-piperidin-1-yl-methanone (F13714; 0.01-1.0 mg/kg) and the 5-HT(2A) receptor agonists 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM; 0.32-10.0 mg/kg) and dipropyltryptamine (DPT; 1.0-32.0 mg/kg), alone and in combination, in rats responding under a fixed ratio schedule of food presentation.
When administered alone, each drug decreased the rate of responding in a dose-related manner with the potency order being F13714 > 8-OH-DPAT > DOM > DPT. WAY100635 (5-HT(1A) receptor antagonist; 0.01-0.1 mg/kg) attenuated the rate-decreasing effects of 8-OH-DPAT and F13714 while MDL100907 (5-HT(2A) receptor antagonist; 0.01-0.1 mg/kg) attenuated the rate-decreasing effects of DOM and DPT. Dose addition analysis showed that the interaction between 8-OH-DPAT and F13714, as well as the interaction between DOM and DPT, was additive. In contrast, the interaction between 8-OH-DPAT and DOM, as well as the interaction between F13714 and DOM, was infra-additive.
This study shows that for some dose combinations, agonist actions at one 5-HT receptor subtype attenuate agonist actions at another 5-HT receptor subtype; thus, the combined neuropharmacological actions and therapeutic effects of indirect-acting agonists are not likely to be adequately characterized by examining in isolation activity at particular 5-HT receptor subtypes.
间接作用的 5-羟色胺（5-HT）受体激动剂（例如选择性 5-HT 再摄取抑制剂 [SSRIs]）会刺激多种 5-HT 受体，但特定受体的作用以及 SSRIs 治疗效果中不同受体之间的相互作用尚不完全清楚。
很少有研究系统地检查直接作用的激动剂的联合使用情况。本研究检测了 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；0.01-10.0mg/kg）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；0.01-1.0mg/kg）以及 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；0.32-10.0mg/kg）和二丙基色胺（DPT；1.0-32.0mg/kg），单独使用和联合使用时，在根据固定比率安排呈现食物的大鼠中，这些药物的作用减少了反应率。
单独给药时，每种药物均以剂量相关的方式降低反应率，其效价顺序为 F13714>8-OH-DPAT>DOM>DPT。WAY100635（5-HT（1A）受体拮抗剂；0.01-0.1mg/kg）减弱了 8-OH-DPAT 和 F13714 的降低反应率作用，而 MDL100907（5-HT（2A）受体拮抗剂；0.01-0.1mg/kg）减弱了 DOM 和 DPT 的降低反应率作用。剂量相加分析表明，8-OH-DPAT 和 F13714 之间的相互作用以及 DOM 和 DPT 之间的相互作用是相加的。相比之下，8-OH-DPAT 和 DOM 之间的相互作用以及 F13714 和 DOM 之间的相互作用是次相加的。
本研究表明，对于某些剂量组合，一种 5-HT 受体亚型的激动剂作用会减弱另一种 5-HT 受体亚型的激动剂作用；因此，间接作用的激动剂的联合神经药理学作用和治疗效果不太可能通过单独检查特定 5-HT 受体亚型的活性来充分描述。
