Neuropsychopharmacology Research Group, School of Pharmacy & Pharmaceutical Sciences and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
Pharmacol Biochem Behav. 2010 Feb;94(4):524-33. doi: 10.1016/j.pbb.2009.11.007. Epub 2009 Nov 26.
The present study determined regional serotonin (5-HT) synthesis and metabolism changes associated with the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine (L-NA) and the influence of 5-HT receptor blockade in the antidepressant-like actions of L-NA in the forced swimming test (FST). Regional effects of L-NA (5,10 and 20mg/kg i.p.) on tryptophan hydroxylase (TPH) activity, the rate limiting enzyme for 5-HT synthesis, were determined by measuring accumulation of the transient intermediate 5-hydoxytryptophan (5-HTP) following in vivo administration of the amino acid decarboxylase inhibitor, NSD 1015 (100mg/kg). L-NA (5-20mg/kg) dose dependently increased 5-HTP accumulation, particularly in the amygdaloid cortex, following exposure to the FST. L-NA also provoked an increase in regional brain 5-HIAA concentrations and in the 5-HIAA:5-HT metabolism ratio. Co-treatment with NSD-1015 failed to consistently modify the antidepressant-like effects of L-NA in the FST. Sub-active doses of L-NA (1mg/kg) and the 5-HT re-uptake inhibitor fluoxetine (2.5mg/kg) acted synergistically to increase swimming in the test. Co-treatment with the non-selective 5-HT receptor antagonist metergoline (1, 2 and 4mg/kg), attenuated the L-NA (20mg/kg)-induced reduction in immobility and increase in swimming behaviours. Metergoline alone however provoked an increase in immobility and reduction in swimming behaviours in the test. A similar response was obtained following co-treatment with the preferential 5-HT(2A) receptor antagonist ketanserin (5mg/kg) and the 5-HT(2C) receptor antagonist RO-430440 (5mg/kg). Co-treatment with the 5-HT(1A) receptor antagonist WAY 100635 (0.3mg/kg) or the 5-HT(1B) receptor antagonist GR 127935 (4mg/kg) failed to influence the antidepressant-like activity of L-NA. Taken together these data provide further support for a role for 5-HT in the antidepressant-like properties of NOS inhibitors.
本研究旨在确定与一氧化氮合酶（NOS）抑制剂 N(G)-硝基-L-精氨酸（L-NA）相关的区域 5-羟色胺（5-HT）合成和代谢变化，以及 5-HT 受体阻断对 L-NA 在强迫游泳试验（FST）中抗抑郁作用的影响。通过测量体内给予氨基酸脱羧酶抑制剂 NSD 1015（100mg/kg）后瞬态中间产物 5-羟色氨酸（5-HTP）的积累，来确定 L-NA（5、10 和 20mg/kg ip）对 5-HT 合成限速酶色氨酸羟化酶（TPH）活性的区域影响。L-NA（5-20mg/kg）剂量依赖性地增加了 5-HTP 的积累，特别是在暴露于 FST 后杏仁核皮质。L-NA 还引起了脑内 5-HIAA 浓度和 5-HIAA：5-HT 代谢比的增加。与 NSD-1015 共同治疗未能一致改变 L-NA 在 FST 中的抗抑郁样作用。亚有效剂量的 L-NA（1mg/kg）和 5-HT 再摄取抑制剂氟西汀（2.5mg/kg）协同作用增加了游泳行为。与非选择性 5-HT 受体拮抗剂麦角林（1、2 和 4mg/kg）共同治疗，减轻了 L-NA（20mg/kg）引起的不动性减少和游泳行为增加。然而，麦角林单独治疗会引起测试中不动性增加和游泳行为减少。在用优先 5-HT(2A)受体拮抗剂酮色林（5mg/kg）和 5-HT(2C)受体拮抗剂 RO-430440（5mg/kg）共同治疗后，也获得了类似的反应。与 5-HT(1A)受体拮抗剂 WAY 100635（0.3mg/kg）或 5-HT(1B)受体拮抗剂 GR 127935（4mg/kg）共同治疗并未影响 L-NA 的抗抑郁样活性。总的来说，这些数据进一步支持 5-HT 在 NOS 抑制剂的抗抑郁样特性中的作用。
