McCreary A C, Bankson M G, Cunningham K A
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, USA.
J Pharmacol Exp Ther. 1999 Sep;290(3):965-73.
The 5-hydroxytryptamine(1B/1D) (5-HT(1B/1D)) antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxyli c acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127935) and 5-HT(1A) antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY 100635) were used to assess whether hyperactivity induced by 3 mg/kg (+)-3, 4-methylenedioxymethamphetamine [(+)-MDMA] is mediated by 5-HT(1B/1D) and/or 5-HT(1A) receptors. Activity in the periphery and center of an open field as well as rearing activity were measured in photobeam monitors. (+)-MDMA-induced peripheral and central activities were blocked by GR 127935 (0.3, 0.625, 1.25, and 2.5 mg/kg); central hyperactivity was blocked by 0.1, 0.3, and 0.625 mg/kg GR 127935. WAY 100635 (0.5-2 mg/kg) had little effect on (+)-MDMA-induced activity except for an enhancement of central activity at one dose (0.5 mg/kg). Central activity induced by (+)-MDMA increased from day 1 to day 5 of treatment with (+)-MDMA (3 mg/kg), whereas peripheral, central, and rearing activity significantly increased in (+)-MDMA-treated rats pretreated daily with GR 127935 (2.5 mg/kg). Withdrawal from (+)-MDMA, but not GR 127935 + (+)-MDMA, pretreatment was associated with heightened hyperactivity induced by the 5-HT(1B/1A) agonist RU 24969 (2 mg/kg i. p.); treatments were not associated with alterations in 5-HT and 5-hydroxyindoleacetic acid content or turnover in frontal cortex. These data support a role for 5-HT(1B/1D) in mediating the acute hyperactivity evoked by (+)-MDMA. The development of sensitization to (+)-MDMA was associated with supersensitivity to a 5-HT(1B/1A) agonist, suggesting that these receptors may contribute to sensitization. However, sensitization to (+)-MDMA developed even under conditions of 5-HT(1B/1D) receptor blockade, which is somewhat counter to this speculation. Perhaps, under circumstances of continued 5-HT(1B/1D) blockade, other mechanisms (e.g., dopamine) predominate in the progressive enhancement of behavior with repeated (+)-MDMA treatment.
使用5-羟色胺（1B/1D）（5-HT(1B/1D)）拮抗剂2'-甲基-4'-(5-甲基-[1,2,4]恶二唑-3-基)-联苯-4-羧酸[4-甲氧基-3-(4-甲基-哌嗪-1-基)-苯基]-酰胺（GR 127935）和5-HT(1A)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）来评估3 mg/kg（+）-3,4-亚甲基二氧甲基苯丙胺[（+）-摇头丸]诱导的多动是否由5-HT(1B/1D)和/或5-HT(1A)受体介导。在光电监测器中测量旷场外周和中央的活动以及竖毛活动。GR 127935（0.3、0.625、1.25和2.5 mg/kg）可阻断（+）-摇头丸诱导的外周和中央活动；0.1、0.3和0.625 mg/kg的GR 127935可阻断中央多动。WAY 100635（0.5 - 2 mg/kg）对（+）-摇头丸诱导的活动影响很小，除了在一个剂量（0.5 mg/kg）时增强了中央活动。在（+）-摇头丸（3 mg/kg）治疗的第1天至第5天，（+）-摇头丸诱导的中央活动增加，而在每天用GR 127935（2.5 mg/kg）预处理的（+）-摇头丸处理的大鼠中，外周、中央和竖毛活动显著增加。停用（+）-摇头丸而非GR 127935 +（+）-摇头丸预处理与5-HT(1B/1A)激动剂RU 24969（2 mg/kg腹腔注射）诱导的多动增强有关；这些处理与额叶皮质中5-羟色胺和5-羟吲哚乙酸含量或周转率的改变无关。这些数据支持5-HT(1B/1D)在介导（+）-摇头丸诱发的急性多动中起作用。对（+）-摇头丸的敏化发展与对5-HT(1B/1A)激动剂的超敏反应有关，表明这些受体可能促成敏化。然而，即使在5-HT(1B/1D)受体阻断的情况下，对（+）-摇头丸的敏化仍会发展，这在一定程度上与这种推测相悖。也许，在持续5-HT(1B/1D)阻断的情况下，其他机制（如多巴胺）在重复（+）-摇头丸治疗后行为的逐渐增强中占主导地位。
