The effects of calcium antagonists on behaviour mediated by 5-hydroxytryptamine (5-HT) have been studied in rats and mice together with an investigation of the effects of these drugs on 5-HT synthesis in rat brain and endogenous 5-HT release from brain slices. 2. Administration of felodipine (35 mg kg-1 i.p.) to rats pretreated with tranylcypromine (20 mg kg-1, i.p.) resulted in the animals displaying the complete 5-HT-mediated behavioural syndrome (including head weaving, reciprocal forepaw treading and hind limb abduction) 75 min later. No evidence was obtained for the rate of 5-HT synthesis in brain regions differing between control and felodipine-treated rats. 3. Pretreatment with felodipine (10 or 35 mg kg-1) enhanced the 5-HT-mediated behavioural syndrome induced by injection of tranylcypromine and L-tryptophan. The rate of 5-HT accumulation in the brain was similar in both groups. Administration of Bay K 8644 (1 mg kg-1, i.p.) did not prevent the enhanced behaviour induced by felodipine (10 mg kg-1). 4. The 5-HT behavioural syndrome induced by injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was unaltered by either acute injection of felodipine (35 mg kg-1) or administration of felodipine twice daily for 3 days. 5. Felodipine (10 microM), verapamil (10 microM) and Bay K 8644 (10 microM) did not alter either basal release of endogenous 5-HT from slices prepared from frontal cortex or hind brain, or release following addition of K+ at a concentration of 20 mM, or 35 mM. 6. Verapamil (25mgkg-', i.p.), nicardipine (25mgkg-1, i.p.) and nifedipine (20mgkg-1, i.p.) all markedly inhibited the 5-HT2 receptor-mediated head twitch response in mice produced by injection of 5- methoxy-N,N-dimethyl-tryptamine (5-MeODMT). Felodipine had the same effect with an ED50 of 2.6mgkg-'. Bay K 8644 did not reverse this effect. Both verapamil (IC50:2.5 microM) and nicardipine (IC50:8 microM) were 5-HT2 antagonists as indicated by inhibition of [3H]-ketanserin binding in mouse frontal cortex. However felodipine and nifedipine antagonized 5-HT2 receptor binding only in the millimolar range.7. Hydralazine (5mg kg 1, i.p.) induced the 5-HT behavioural syndrome in tranylcypromine pretreated rats, enhanced the tranylcypromine/L-tryptophan behavioural syndrome, inhibited 5-MeODMT-induced head twitch behaviour in mice and was not a 5-HT2 receptor antagonist. 8. These data indicate that at a high dose, Ca2+ antagonists produce complex changes in 5-HT function in rodents which are similar to those produced by lithium administration. The data with hydralazine suggest that the effects seen are not related to an action at Ca2 + channels.
摘要
研究了钙拮抗剂对5-羟色胺（5-HT）介导行为的影响，同时还研究了这些药物对大鼠脑内5-HT合成以及脑片内源性5-HT释放的影响，实验对象为大鼠和小鼠。2. 给用反苯环丙胺（20mg/kg，腹腔注射）预处理过的大鼠腹腔注射非洛地平（35mg/kg），75分钟后动物出现了完全由5-HT介导的行为综合征（包括头部摆动、前爪交替踩踏和后肢外展）。未发现对照组和非洛地平处理组大鼠脑区5-HT合成速率存在差异。3. 用非洛地平（10或35mg/kg）预处理可增强由注射反苯环丙胺和L-色氨酸诱导的5-HT介导的行为综合征。两组脑内5-HT积累速率相似。腹腔注射Bay K 8644（1mg/kg）不能阻止非洛地平（10mg/kg）诱导的行为增强。4. 注射5-HT1A激动剂8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）诱导的5-HT行为综合征，无论是急性注射非洛地平（35mg/kg）还是连续3天每天注射两次非洛地平，均未改变。5. 非洛地平（10μM）、维拉帕米（10μM）和Bay K 8644（10μM）既不改变额叶皮质或后脑切片内源性5-HT的基础释放，也不改变加入浓度为20mM或35mM钾离子后的释放。6. 维拉帕米（25mg/kg，腹腔注射）、尼卡地平（25mg/kg，腹腔注射）和硝苯地平（20mg/kg，腹腔注射）均能显著抑制注射5-甲氧基-N,N-二甲基色胺（5-MeODMT）所致小鼠5-HT2受体介导的头部抽搐反应。非洛地平也有同样作用，半数有效剂量为2.6mg/kg。Bay K 8644不能逆转此作用。如对小鼠额叶皮质[3H]-酮色林结合的抑制所示，维拉帕米（半数抑制浓度：2.5μM）和尼卡地平（半数抑制浓度：8μM）均为5-HT2拮抗剂。然而，非洛地平和硝苯地平仅在毫摩尔范围内拮抗5-HT2受体结合。7. 肼屈嗪（5mg/kg，腹腔注射）在反苯环丙胺预处理的大鼠中诱导出5-HT行为综合征，增强了反苯环丙胺/L-色氨酸行为综合征，抑制了小鼠5-MeODMT诱导的头部抽搐行为，且不是5-HT2受体拮抗剂。8. 这些数据表明，高剂量时钙拮抗剂在啮齿动物中会引起5-HT功能的复杂变化，这与锂给药产生的变化相似。肼屈嗪的数据表明所观察到的效应与作用于钙通道无关。
