ALTERATION OF SEROTONIN RELEASE IN THE GUINEA-PIG ORBITOFRONTAL CORTEX BY SELECTIVE SEROTONIN REUPTAKE INHIBITORS - RELEVANCE TO TREATMENT OF OBSESSIVE-COMPULSIVE DISORDER
ALTERATION OF SEROTONIN RELEASE IN THE GUINEA-PIG ORBITOFRONTAL CORTEX BY SELECTIVE SEROTONIN REUPTAKE INHIBITORS - RELEVANCE TO TREATMENT OF OBSESSIVE-COMPULSIVE DISORDER
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DOI：
10.1016/0893-133x(95)00045-f
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发表时间：
1995-10-01
影响因子：
7.6
通讯作者：
BLIER, P
中科院分区：
文献类型：
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作者：
ELMANSARI, M;BOUCHARD, C;BLIER, P
强效血清素 (5-HT) 再摄取抑制剂是迄今为止唯一被证明可有效治疗强迫症 (OCD) 的抗抑郁药物。对人类的正电子发射断层扫描研究表明，眶额皮质和尾状核头部与强迫症症状的调节有关。由于选择性 5-HT 再摄取抑制剂 (SSRI) 最大治疗效果的延迟在强迫症中比在重度抑郁症中更长，并且 SSRI 给药 3 周后，豚鼠额叶皮层中的末端 5-HT 自身受体并未脱敏，因此 SSRI 帕罗西汀（10 mg/kg/天）和氟西汀（5 mg/kg/天）对 5-HT 释放和末端 5-HT 敏感性的影响在治疗 3 周和 8 周后的清除期后，对豚鼠额叶皮质、眶额皮质和尾状核头部的 5-HT 自身受体进行了研究。在用帕罗西汀治疗 3 周的豚鼠制备的预加载切片中，额叶皮质 (21%) 的电诱发释放 [H-3]5-HT 释放增强，但在眶额皮质或尾状核头部没有增强。然而，经过8周的治疗后，同一动物的眶额皮质（55％）和额叶皮质的其余部分（29％）的[H-3]5-HT诱发释放显着增强，但尾状核头部仍然没有变化。用 5-HT 自身受体激动剂 5-甲氧基色胺构建的浓度效应曲线表明，帕罗西汀治疗 8 周后，仅在眶额皮质中末端 5-HT 自身受体脱敏。此外，5-HT 转运蛋白在额叶皮层中脱敏，但在眶额皮层中却没有。在氟西汀治疗 3 周或 8 周的情况下，眶额皮质和尾状核头部的 [H-3]5-HT 释放和末端 5-HT 自身受体的敏感性均未改变。这可能是由于氟西汀对 5-HT 再摄取的抑制程度较小，这与改善强迫症通常需要比抑郁症更高剂量的 SSRI 的观点相一致。综上所述，这些结果表明，在眶额皮质中，长期且显着的 5-HT 再摄取抑制诱导的 [H-3]5-HT 释放增强可归因于末端 5-HT 自身受体的脱敏。
Potent serotonin (5-HT) reuptake inhibitors are the only antidepressant agents thus far shown to be effective in the treatment of obsessive-compulsive disorder (OCD). Positron emission tomography studies in humans have implicated the orbito-frontal cortex and the head of caudate nucleus in the mediation of OCD symptoms. Since the delay of the maximal therapeutic effect of selective 5-HT reuptake inhibitors (SSRI) is longer in OCD than in major depression and the terminal 5-HT autoreceptor is not desensitized in the guinea pig frontal cortex after 3 weeks of SSRI administration, the effects of the SSRI paroxetine (10 mg/kg/day) and fluoxetine (5 mg/kg/day) on 5-HT release and on the sensitivity of the terminal 5-HT autoreceptor were investigated in the guinea pig frontal cortex, the orbito-frontal cortex, and the head of caudate nucleus following a washout period after 3 and 8 weeks of treatment. In preloaded slices prepared from guinea pigs treated with paroxetine for 3 weeks, the electrically evoked release of [H-3]5-HT release was enhanced in the frontal cortex (21%) but not in the orbito-frontal cortex or in the head of caudate nucleus. However, after an 8-week treatment, the evoked release of [H-3]5-HT was significantly enhanced in the orbito-frontal cortex (55%) and in the rest of the frontal cortex (29%) from the same animals, but still unchanged in the head of caudate nucleus. Concentration-effect curves, constructed with the 5-HT autoreceptor agonist 5-methoxytryptamine, showed that the terminal 5-HT autoreceptor was desensitized only in the orbito-frontal cortex after 8 weeks of treatment with paroxetine. Furthermore, the 5-HT transporter was desensitized in the frontal cortex but not in the orbito-frontal cortex. In the case of 3- or 8-week fluoxetine treatment, neither [H-3]5-HT release nor the sensitivity of the terminal 5-HT autoreceptor were altered in the orbito-frontal cortex and the head of caudate nucleus. This could be attributable to a smaller degree of 5-HT reuptake inhibition achieved with fluoxetine, in keeping with the notion that higher doses of SSRI are generally required to improve OCD than depression. Taken together, these results indicate that, in the orbito-frontal cortex, the enhanced release of [H-3]5-HT induced by prolonged and marked 5-HT reuptake inhibition is attributable to a desensitization of the terminal 5-HT autoreceptor.