西布曲明的代谢产物BTS 54,505对大鼠背外侧膝状核体内单胺和兴奋性氨基酸诱发反应的影响。

The effects of BTS 54,505, a metabolite of sibutramine, on monoamine and excitatory amino acid-evoked responses in the rat dorsolateral geniculate nucleus in vivo.

作者信息

Scott G, Luscombe G P, Mason R

机构信息

Department of Physiology and Pharmacology, University of Nottingham Medical School, Queens Medical Centre.

出版信息

Br J Pharmacol. 1994 Jan;111(1):97-102. doi: 10.1111/j.1476-5381.1994.tb14029.x.

DOI:10.1111/j.1476-5381.1994.tb14029.x

PMID:7516805

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1910041/

Abstract

The effects of BTS 54,505, the primary amine metabolite of the non-tricylic putative antidepressant sibutramine, on the responses evoked by visual stimulation and ionophoretic application of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and excitatory amino acids (EAAs) in the rat dorsolateral geniculate nucleus (dLGN) have been investigated. 2. Ionophoretic application of 5-HT to dLGN neurones attenuated visually-evoked (n = 46), NMDA-evoked (n = 21) and AMPA-evoked responses (n = 21), while ionophoretic application of NA potentiated visually-evoked activity in these cells (n = 27). 3. Simultaneous application of BTS 54,505 with 5-HT (over 120 s) resulted in a prolongation of the recovery time (i.e. the period required by a neurone to recover by 50%, RT50) from the 5-HT-mediated suppression of discharge activity (approximately 275% increase in RT50). BTS 54,505 also prolonged the recovery time from a NA-mediated potentiation of firing (approximately 450% increase in RT50). These effects on recovery time are attributed to the inhibition of uptake of both 5-HT and NA by BTS 54,505. The amplitude of the response to 5-HT or NA was unaffected by co-ejection of BTS 54,505. 4. Ionophoretic application of N-methyl-D-aspartate (NMDA) produced a current-dependent increase in neuronal firing, as did application of the non-NMDA receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). A simultaneous 120 s application of BTS 54,505 inhibited the NMDA response in all cells studied (mean ED50 = 16 +/- 5 nA) but had no effect on AMPA-evoked activity in the majority of the same cells (n = 15/21).5. Short 10 s applications of BTS 54 505, at ejecting currents (>30 nA) that attenuated NMDA-evoked activity in all cells studied, had no effect on either response amplitude or recovery time from ionophoretic application of 5-HT, suggesting that inhibition of NMDA-evoked activity by BTS 54 505 was not mediated by 5-HT uptake blockade.6. These results suggest that BTS 54 505 inhibits NMDA-evoked activity, and the observation that this effect is unlikely to be due to raised levels of endogenous 5-HT following monoamine uptake blockade indicate that BTS 54 505 may interact directly with the NMDA receptor ionophore complex.

摘要

已对非三环类假定抗抑郁药西布曲明的主要胺类代谢物BTS 54,505对大鼠背外侧膝状核（dLGN）中视觉刺激以及去甲肾上腺素（NA）、5-羟色胺（5-HT）和兴奋性氨基酸（EAA）离子导入所诱发反应的影响进行了研究。2. 对dLGN神经元进行5-HT离子导入可减弱视觉诱发反应（n = 46）、NMDA诱发反应（n = 21）和AMPA诱发反应（n = 21），而NA离子导入则增强这些细胞中的视觉诱发活动（n = 27）。3. BTS 54,505与5-HT同时应用（持续120秒）导致从5-HT介导的放电活动抑制中恢复的时间（即神经元恢复50%所需的时间，RT50）延长（RT50增加约275%）。BTS 54,505还延长了从NA介导的放电增强中恢复的时间（RT50增加约450%）。对恢复时间的这些影响归因于BTS 54,505对5-HT和NA摄取的抑制。BTS 54,505共同注射对5-HT或NA反应的幅度没有影响。4. N-甲基-D-天冬氨酸（NMDA）离子导入产生了与电流相关的神经元放电增加，非NMDA受体激动剂α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）的应用也产生了这种情况。同时应用120秒的BTS 54,505抑制了所有研究细胞中的NMDA反应（平均ED50 = 16 +/- 5 nA），但对大多数相同细胞（n = 15/21）中的AMPA诱发活动没有影响。5. 在所有研究细胞中，以减弱NMDA诱发活动的喷射电流（>30 nA）进行10秒的BTS 54 505短时间应用，对5-HT离子导入的反应幅度或恢复时间均无影响，这表明BTS 54 505对NMDA诱发活动的抑制不是由5-HT摄取阻断介导的。6. 这些结果表明BTS 54 505抑制NMDA诱发的活动，并且这种效应不太可能是由于单胺摄取阻断后内源性5-HT水平升高所致，这一观察结果表明BTS 54 505可能直接与NMDA受体离子通道复合物相互作用。