Indirect in vivo 5-HT1A-agonistic effects of the new antidepressant mirtazapine
Indirect in vivo 5-HT1A-agonistic effects of the new antidepressant mirtazapine
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DOI：
10.1007/s002130050402
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发表时间：
1997-10-01
影响因子：
3.4
通讯作者：
Broekkamp, CLE
中科院分区：
文献类型：
--
作者：
Berendsen, HHG;Broekkamp, CLE
新的抗抑郁药米氮平在两个实验程序中进行了测试，可以揭示直接或间接的5-HT 1A受体激动作用。观察这些程序诱导大鼠下唇退缩和比较刺激特性的交叉熟悉实验与条件性味觉厌恶的小鼠。米氮平诱导大鼠下唇退缩，5-HT 1A受体激动剂（+/-）-8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）也是如此。然而，剂量高达22 mg/kg的米氮平的反应仍低于8-OH-DPAT（0.46 mg/kg）获得的最大评分。用吲哚洛尔（10 mg/kg）阻断5-HT 1A受体可显著减少米氮平和8-OH-DPAT诱导的下唇退缩。在交叉熟悉条件性味觉厌恶实验中发现，如果小鼠预先注射米氮平（0.22和0.46 mg/kg）、8-OH-DPAT（0.22和0.46 mg/kg）和预先暴露于5-HT再摄取抑制剂氟西汀（22 mg/kg），则可以预防米氮平（0.32 mg/kg）诱导的条件性味觉厌恶。通过预先暴露于（+/-）1-（2，5-二甲氧基-4-碘苯基）-2-氨基丙烷盐酸盐（DOI）（0.46-4.6 mg/kg）和MK 212（2.2-22 mg/kg）（分别为5-HT 2A和5-HT 2C受体的激动剂），未获得对米氮平刺激的熟悉。按照相反的顺序，预先暴露于1 mg/kg的米氮平仅能部分预防8-OH-DPAT（0.22 mg/kg）、DOI（1.0 mg/kg）和氟西汀诱导的条件性味觉厌恶。MK 212（4.6 mg/kg）诱导的条件性味觉厌恶不受预先暴露于米氮平（0.1-1.0 mg/kg）的影响。根据这些结果，可以得出结论，米氮平具有间接的5-HT 1A受体激动剂特性，这可能在该化合物的治疗效果中发挥重要作用。
The new antidepressant mirtazapine was tested in two experimental procedures which can reveal direct or indirect 5-HT1A receptor agonistic effects. These procedures were observation for induction of lower lip retraction in rats and comparison of stimulus properties in cross-familiarization experiments with conditioned taste aversion in mice. Mirtazapine induced lower lip retraction in rats, as did the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). However, the response to mirtazapine at doses up to 22 mg/kg remained below the maximum score obtained with 8-OH-DPAT (0.46 mg/kg). Blockade of the 5-HT1A receptors with pindolol (10 mg/kg) caused a strong reduction of the lower lip retraction induced both with mirtazapine and 8-OH-DPAT. In the cross-familiarization conditioned taste aversion experiments it was found that the conditioned taste aversion induced by mirtazapine (0.32 mg/kg) could be prevented if the mice were preexposed to injections with mirtazapine (0.22 and 0.46 mg/kg), 8-OH-DPAT (0.22 and 0.46 mg/kg) and after pre-exposure to the 5-HT reuptake inhibitor fluoxetine (22 mg/kg). No familiarization for the mirtazapine stimulus was obtained by pre-exposure to (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) (0.46-4.6 mg/kg) and MK212 (2.2-22 mg/kg), being agonists for the 5-HT2A and 5-HT2C receptors, respectively. With the reversed sequence, the conditioned taste aversion induced by 8-OH-DPAT (0.22 mg/kg), DOI (1.0 mg/kg) and fluoxetine could be prevented only partially by pre-exposure to mirtazapine in a dose of 1 mg/kg. The conditioned taste aversion induced by MK 212 (4.6 mg/kg) was not affected by pre-exposure to mirtazapine (0.1-1.0 mg/kg). On the basis of these results, it can be concluded that mirtazapine has indirect 5-HT1A receptor agonistic properties which may play an important role in the therapeutic effect of this compound.