EVIDENCE THAT RU-24969-INDUCED LOCOMOTOR-ACTIVITY IN C57/B1/6 MICE IS SPECIFICALLY MEDIATED BY THE 5-HT(1B) RECEPTOR
EVIDENCE THAT RU-24969-INDUCED LOCOMOTOR-ACTIVITY IN C57/B1/6 MICE IS SPECIFICALLY MEDIATED BY THE 5-HT(1B) RECEPTOR
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DOI：
10.1111/j.1476-5381.1993.tb14010.x
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发表时间：
1993-12-01
影响因子：
7.3
通讯作者：
HEAL, DJ
中科院分区：
文献类型：
--
作者：
CHEETHAM, SC;HEAL, DJ
1 5-HT1B 受体激动剂 RU 24969 和 CGS 12066B 的行为效应已在 C57/B1/6 小鼠中进行了研究。2 RU 24969 (1 - 30 mg kg-1) 产生强烈且持久的过度运动和其他行为变化。3 CGS 12066B 引起类似的效应，但无论该药物是否为给定IP (1-15 mg kg-1) 或 i.c.v. （0.2-40 杯）。然而，CGS 12066B (7.5 和 15 mg kg-1) 对 RU 24969 (7.5 mg kg-1) 诱导的过度运动产生剂量相关的抑制，表明前者是 5-HT1B 部分激动剂。4 RU 24969 (7.5 mg kg-1 i.p.) 诱导的过度运动被 (-)- 抑制，但异构体不被抑制。吲哚洛尔 (4 mg kg-1) 和普萘洛尔 (20 mg kg-1)，但美托洛尔 (10 mg kg-1) 或 ICI 118,551 (5 mg kg-1) 不受影响，与 5-HT1A 或 5-HT1B 受体的参与一致。5 选择性 5-HT1A 受体拮抗剂 WAY 100135（5 mg kg-1， s.c.）、5-HT2A/5-HT2c 受体拮抗剂利坦色林（0.1 mg kg-1）、选择性 5-HT3 受体拮抗剂昂丹司琼（1 mg kg-1）或非选择性 5-HT 受体拮抗剂美西麦角（3 mg kg-1）和米角林（3 mg kg-1）。 6 尽管螺沙林（0.1 mg kg-1）和酮舍林 (1 mg kg-1) 抑制 RU 24969 诱导的过度运动，这些作用可能分别是由于多巴胺 D2 受体和 α1-肾上腺素受体的拮抗作用所致。7 总而言之，这些结果表明 RU 24969 诱导的过度运动特别是由中枢 5-HT1B 受体的激活引起的。8 5-HT 神经元的损伤5,7-二羟基色胺（75 杯，静脉注射）或消耗对氯苯丙氨酸（200 mg kg-1，腹膜内注射 14 天）对 RU 24969 诱导的过度运动没有影响，证明所涉及的 5-HT1B 受体是突触后的，并且它们不表现出超敏感性。 9 RU 中其他单胺神经递质系统的参与还检查了 24969 诱导的过度运动。该反应被 α1 肾上腺素受体拮抗剂哌唑嗪 (1 mg kg-1)、多巴胺 D1 受体拮抗剂 SCH 23390 (0.05 mg kg-1) 和多巴胺 D2 受体拮抗剂 BRL 34778 (0.03 mg kg-1) 抑制，但不被 α2 肾上腺素受体拮抗剂咪唑克生 (1 mg kg-1) 抑制。用 N-(2-氯乙基)-N-乙基-2-溴苄胺 (100 mg kg-1) 损伤去甲肾上腺素能神经元可显着减弱这种行为。这些结果表明，过度运动是通过作用于 α1-肾上腺素能受体、D1 和 D2 受体的去甲肾上腺素能和多巴胺能神经元表达的。10 RU 24969 降低了大脑中 5-羟基吲哚乙酸的浓度，同时增加了 5-HT，这与通过激活 5-HT1A 和 5-HT1B 自身受体而减少 5-HT 神经元活性一致。 RU 24969 增加了脑中 3-甲氧基-4-羟基苯基乙二醇的浓度，但不增加去甲肾上腺素的浓度，这支持去甲肾上腺素能神经元参与过度运动的表达。 RU 24969 没有改变伏隔核中的多巴胺、二羟基苯乙酸或高香草酸浓度，表明终止在那里的多巴胺能神经元没有直接参与。
1 The behavioural effects of the 5-HT1B receptor agonists, RU 24969 and CGS 12066B, have been investigated in C57/B1/6 mice.2 RU 24969 (1 - 30 mg kg-1) produced intense and prolonged hyperlocomotion and other behavioural changes.3 CGS 12066B caused similar effects, but they were much less pronounced, inconsistent and transient irrespective of whether this drug was given i.p. (1-15 mg kg-1) or i.c.v. (0.2-40 mug). However, CGS 12066B (7.5 and 15 mg kg-1) caused a dose-related inhibition of RU 24969 (7.5 mg kg-1)-induced hyperlocomotion indicating that the former is a 5-HT1B partial agonist.4 RU 24969 (7.5 mg kg-1 i.p.)-induced hyperlocomotion was inhibited by the (-)-, but not isomers of pindolol (4 mg kg-1) and propranolol (20 mg kg-1) but not by metoprolol (10 mg kg-1) or ICI 118,551 (5 mg kg-1), consistent with an involvement of 5-HT1A or 5-HT1B receptors.5 The response was not altered by the selective 5-HT1A receptor antagonist, WAY 100135 (5 mg kg-1, s.c.), the 5-HT2A/5-HT2c receptor antagonist, ritanserin (0.1 mg kg-1), the selective 5-HT3 receptor antagonist, ondansetron (1 mg kg-1) or the non-selective 5-HT receptor antagonists methysergide (3 mg kg-1) and metergoline (3 mg kg-1).6 Although spiroxatrine (0.1 mg kg-1) and ketanserin (1 mg kg-1) inhibited RU 24969-induced hyperlocomotion, these effects were probably due to antagonism of dopamine D2 receptors and alpha1-adrenoceptors respectively.7 Taken together, these results indicate that RU 24969-induced hyperlocomotion results specifically from activation of central 5-HT1B receptors.8 Lesioning of 5-HT neurones with 5,7-dihydroxytryptamine (75 mug, i.c.v.) or depletion with p-chlorophenylalanine (200 mg kg-1, i.p. for 14 days) had no effect on RU 24969-induced hyperlocomotion demonstrating that the 5-HT1B receptors involved are postsynaptic and that they do not show supersensitivity.9 The involvement of other monoamine neurotransmitter systems in RU 24969-induced hyperlocomotion was also examined. The response was inhibited by the alpha1-adrenoceptor antagonist, prazosin (1 mg kg-1), the dopamine D1 receptor antagonist, SCH 23390 (0.05 mg kg- 1) and the dopamine D2 receptor antagonist, BRL 34778 (0.03 mg kg-1), but not by the alpha2-adrenoceptor antagonist, idazoxan (1 mg kg-1). Lesioning noradrenergic neurones with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (100 mg kg-1) markedly attenuated this behaviour. These results show that the hyperlocomotion is expressed via noradrenergic and dopaminergic neurones acting on alpha1-adrenoceptors, D1 and D2 receptors.10 RU 24969 decreased brain concentrations of 5-hydroxyindoleacetic acid whilst simultaneously increasing 5-HT, consistent with the reduction of 5-HT neuronal activity by activation of 5-HT1A and 5-HT1B autoreceptors. RU 24969 increased brain 3-methoxy-4-hydroxyphenylglycol, but not noradrenaline, concentrations which supports the involvement of noradrenergic neurones in the expression of hyperlocomotion. RU 24969 did not alter dopamine, dihydroxyphenylacetic acid or homovanillic acid concentrations in the nucleus accumbens suggesting that the dopaminergic neurones terminating there are not directly involved.