Sustained pharmacological blockade of NK1 substance P receptors causes functional desensitization of dorsal raphe 5-HT1A autoreceptors in mice
Sustained pharmacological blockade of NK1 substance P receptors causes functional desensitization of dorsal raphe 5-HT1A autoreceptors in mice
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DOI：
10.1111/j.1471-4159.2005.03488.x
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发表时间：
2005-12-01
影响因子：
4.7
通讯作者：
Lanfumey, L
中科院分区：
文献类型：
--
作者：
Guiard, BP;Froger, N;Lanfumey, L
NK1 P物质受体拮抗剂在动物和人类中都表现出与选择性5-羟色胺再摄取抑制剂（SSRIs）相似的抗抑郁特性，后者可诱导中脑背核（DRN）内5-HT1A自身受体脱敏。我们研究了这种受体适应是否也发生在NK1受体阻断的情况下。用选择性NK1受体拮抗剂GR 205171（每天10 mg/kg）通过皮下植入渗透性微型泵治疗C57B/L6J小鼠21天，采用多种方法评估DRN 5-HT1A自身受体功能。脑干切片中DRN - 5-羟色胺能神经元的记录显示，GR 205171处理降低了5-HT1A受体激动剂ipsapione抑制细胞放电的效力（约1.5倍）。同时，GR 205171处理小鼠脑干部分DRN上5-HT1A自受体介导的[S-35] gtp - γ - s结合显著降低。体内微透析显示，急性注射SSRI帕罗西汀（1mg /kg）引起的皮质5-羟色胺溢出在GR 205171治疗组是对照组的两倍。在DRN中，GR 205171治疗显著增强了基础5-HT流出。这些数据支持了慢性NK1受体阻断诱导5-HT1A自受体功能脱敏的假设，类似于在SSRIs中观察到的。
Antagonists at NK1 substance P receptors have demonstrated similar antidepressant properties in both animal paradigms and in human as selective serotonin reuptake inhibitors (SSRIs) that induce desensitization of 5-HT1A autoreceptors within the dorsal raphe nucleus (DRN). We investigated whether this receptor adaptation also occurs upon NK1 receptor blockade. C57B/L6J mice were treated for 21 days with the selective NK1 receptor antagonist GR 205171 (10 mg/kg daily) through subcutaneously implanted osmotic mini pumps, and DRN 5-HT1A autoreceptor functioning was assessed using various approaches. Recording of DRN serotonergic neurons in brainstem slices showed that GR 205171 treatment reduced (by similar to 1.5 fold) the potency of the 5-HT1A receptor agonist, ipsapirone, to inhibit cell firing. In parallel, the 5-HT1A autoreceptor-mediated [S-35]GTP-gamma-S binding induced by 5-carboxamidotryptamine onto the DRN in brainstem sections was significantly decreased in GR 205171-treated mice. In vivo microdialysis showed that the cortical 5-HT overflow caused by acute injection of the SSRI paroxetine (1 mg/kg) was twice as high in GR 205171-treated as in vehicle-treated controls. In the DRN, basal 5-HT outflow was significantly enhanced by GR 205171 treatment. These data supported the hypothesis that chronic NK1 receptor blockade induces a functional desensitization of 5-HT1A autoreceptors similar to that observed with SSRIs.