Stress-induced increase of cortical dopamine metabolism:: attenuation by a tachykinin NK1 receptor antagonist
Stress-induced increase of cortical dopamine metabolism:: attenuation by a tachykinin NK1 receptor antagonist
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DOI：
10.1016/j.ejphar.2003.10.057
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发表时间：
2004-01-19
影响因子：
5
通讯作者：
Barton, CL
中科院分区：
文献类型：
--
作者：
Hutson, PH;Patel, S;Barton, CL
本研究检测了速激肽NK1受体在调节束缚应激诱导的大鼠内侧前额叶皮质多巴胺代谢增加中的潜在作用。与以前的研究一致，20min的束缚应激显著增加内侧前额叶皮质的多巴胺代谢，这反映在多巴胺代谢物二羟基苯乙酸(DOPAC)的浓度上。预先给予高亲和力、选择性、速激肽NK1受体拮抗剂(3(S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethyl氨基)-2(S)-苯基哌啶(S)-GR205171，10 mg/kg，S.C.，体外结合研究中广泛占据大鼠脑速激肽NK1受体约60min，显著减弱应激诱导的中皮质DOPAC浓度升高，而本身不影响大脑皮层DOPAC水平。相比之下，用活性较低的对映体(R)-GR205171(10 mg/kg，S.C.)预处理的动物，其体外快速激肽NK1受体的占有率可以忽略不计，但未能影响基础或应激诱导的内侧前额叶皮质中DOPAC的浓度。此外，动物预先给予苯二氮卓类/氨基丁酸(A)受体拮抗剂氟马西尼(15 mg/kg，ip)，不影响(S)-GR205171减轻急性应激引起的内侧前额叶皮质DOPAC浓度升高的能力。结果表明，选择性速激肽NK1受体拮抗剂(S)-GR205171可减弱应激诱导的中皮质多巴胺神经元的激活，其机制不依赖于GABA(A)受体的苯二氮卓类调节部位。(C)2003爱思唯尔B.V.保留所有权利。
The present study examined the potential role of tachykinin NK1 receptors in modulating immobilisation stress-induced increase of dopamine metabolism in rat medial prefrontal cortex. In agreement with previous studies, 20 min immobilisation stress significantly increased medial prefrontal cortex dopamine metabolism as reflected by the concentration of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC). Pretreatment with the high affinity, selective, tachykinin NK1 receptor antagonist (3(S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethyl amino)-2(S)-phenylpiperidine) ((S)-GR205171, 10 mg/kg, s.c.), a dose that in ex vivo binding studies extensively occupied rat brain tachykinin NK1 receptors for approximately 60 min, significantly attenuated the stress-induced increase of mesocortical DOPAC concentration without affecting cortical DOPAC levels per se. In contrast, pretreatment of animals with the less active enantiomer (R)-GR205171 (10 mg/kg, s.c.), which demonstrated negligible tachykinin NK1 receptor occupancy ex vivo, failed to affect either basal or stress-induced DOPAC concentration in medial prefrontal cortex. Furthermore, pretreatment of animals with the benzodiazepine/GABA(A) receptor antagonist, flumazenil (15 mg/kg, i.p.), did not affect the ability of (S)-GR205171 to attenuate the increase of medial prefrontal cortex DOPAC concentration by acute stress. Results demonstrate that the selective tachykinin NK1 receptor antagonist, (S)-GR205171, attenuated the stress-induced activation of mesocortical dopamine neurones by a mechanism independent of the benzodiazepine modulatory site of the GABA(A) receptor. (C) 2003 Elsevier B.V All rights reserved.