Durand M, Berton O, Aguerre S, Edno L, Combourieu I, Mormède P, Chaouloff F
NeuroGénétique et Stress, INSERM U471-INRA, Institut François Magendie, Bordeaux, France.
Neuropharmacology. 1999 Jun;38(6):893-907. doi: 10.1016/s0028-3908(99)00009-x.
In keeping with the anxiolytic property of selective serotonin reuptake inhibitors (SSRIs) in humans, we have examined in the spontaneously hypertensive rat (SHR) and the Wistar-Kyoto (WKY) rat, which display low and high anxiety, respectively, some psychoneuroendocrine effects of a repeated treatment with the SSRI fluoxetine (5 or 10 mg/kg daily, for 3 weeks). Two days after the last injection, plasma levels of fluoxetine were not detectable whereas those of its metabolite, norfluoxetine, were present to similar extents in both strains. By means of the elevated plus-maze test (29-30 h after the 13th administration of fluoxetine) and an open field test (48 h after the last injection of fluoxetine), it was observed that fluoxetine pretreatment did not yield anxiolysis; hence, some, but not all, behaviours were indicative of anxiety and hypolocomotion (as assessed through principal component analyses and acute diazepam studies). In both strains, the 10 mg/kg dose of fluoxetine decreased hypothalamus 5-HT and 5-HIAA levels, and reduced midbrain and/or hippocampus [3H]citalopram binding at 5-HT transporters, but did not affect [3H]8-hydroxy-2-(di-N-propylamino)tetralin binding at hippocampal 5-HT1A receptors. However, the fluoxetine-elicited reduction in hippocampal 5-HT transporter binding was much more important in WKY than in SHR rats, this strain-dependent effect being associated in WKY rats with a reduction in cortical [3H]ketanserin binding at 5-HT2A receptors. Lastly, in WKY rats, repeated fluoxetine administration increased adrenal weights and the plasma corticosterone response to open field exposure, but did not affect the binding capacities of hippocampal mineralocorticoid and glucocorticoid receptors. These data show that key psychoneuroendocrine responses to repeated fluoxetine administration may be strain-dependent, and that repeated fluoxetine administration does not yield anxiolysis, as assessed by two standard tests of emotivity.
为了与选择性5-羟色胺再摄取抑制剂（SSRIs）对人类的抗焦虑特性保持一致，我们在分别表现出低焦虑和高焦虑的自发性高血压大鼠（SHR）和Wistar-Kyoto（WKY）大鼠中，研究了用SSRI氟西汀（每日5或10mg/kg，共3周）重复治疗的一些精神神经内分泌效应。在最后一次注射后两天，未检测到氟西汀的血浆水平，而其代谢产物去甲氟西汀的血浆水平在两种品系中均以相似程度存在。通过高架十字迷宫试验（在第13次给予氟西汀后29 - 30小时）和旷场试验（在最后一次注射氟西汀后48小时）观察到，氟西汀预处理并未产生抗焦虑作用；因此，一些（但并非全部）行为表明存在焦虑和运动减少（通过主成分分析和急性地西泮研究评估）。在两种品系中，10mg/kg剂量的氟西汀降低了下丘脑5-羟色胺（5-HT）和5-羟吲哚乙酸（5-HIAA）水平，并降低了中脑和/或海马体中5-HT转运体的[3H]西酞普兰结合，但不影响海马体5-HT1A受体处的[3H]8-羟基-2-（二-N-丙基氨基）四氢萘（[3H]8-OH-DPAT）结合。然而，氟西汀引起的海马体5-HT转运体结合减少在WKY大鼠中比在SHR大鼠中更为显著，这种品系依赖性效应在WKY大鼠中与皮质5-HT2A受体处的[3H]酮色林结合减少有关。最后，在WKY大鼠中，重复给予氟西汀增加了肾上腺重量以及血浆皮质酮对旷场暴露的反应，但不影响海马体盐皮质激素和糖皮质激素受体的结合能力。这些数据表明，重复给予氟西汀后的关键精神神经内分泌反应可能具有品系依赖性，并且如通过两种标准情绪测试所评估的，重复给予氟西汀不会产生抗焦虑作用。
