Anti-anhedonic effect of selective serotonin reuptake inhibitors with affinity for sigma-1 receptors in picrotoxin-treated mice
Anti-anhedonic effect of selective serotonin reuptake inhibitors with affinity for sigma-1 receptors in picrotoxin-treated mice
复制标题
与 sigma-1 受体有亲和力的选择性血清素再摄取抑制剂对印防己毒素处理的小鼠的抗快感缺乏作用
DOI：
10.1111/bph.13692
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发表时间：
2017
影响因子：
7.3
通讯作者：
Matsuda T
中科院分区：
文献类型：
--
作者：
Hasebe S;Ago Y;Watabe Y;Oka S;Hiramatsu N;Tanaka T;Umehara C;Hashimoto H;Takuma K;Matsuda T
背景和目的GABA受体拮抗剂印防己毒素可增强5-HTA1和σ-1受体联合激活的前额叶多巴胺释放。在这里，我们检查了这种神经化学事件是否伴随着行为变化。实验方法：用印防己毒素处理雄性小鼠以降低GABAA受体功能。他们的非享乐性行为是通过女性相遇测试来衡量的。免疫组织化学方法检测c-Fos的表达。关键结果：印防己毒素对大鼠三种行为测试均有致焦虑作用，但对强迫游泳实验中的不动时间无明显影响。印防己毒素降低了雌性在雌性相遇实验中的偏好，并减弱了雌性相遇引起的伏隔核c-Fos表达的增加。对σ-1受体具有高亲和力的选择性5-羟色胺再摄取抑制剂氟伏沙明和(+)-氟西汀可改善印防己毒素所致的快感障碍。氟伏沙明的作用可被5-HT1受体拮抗剂或σ1受体拮抗剂阻断，σ1受体激动剂(+)-SKF-10047和5-HT1受体激动剂奥斯莫唑坦的作用与氟伏沙明相似。相比之下，地塞帕明、度洛西汀和帕罗西汀对σ-1受体几乎没有亲和力，并不影响印防己毒素引起的快感丧失。多巴胺D2/3受体拮抗剂可阻断氟伏沙明的作用。前额叶多巴胺系统的激活剂哌醋甲酯可改善印防己毒素引起的快感障碍。结论和意义印防己毒素处理的小鼠表现出快感障碍行为，这种行为通过同时激活5-HT1A和σ-1受体而得到改善。这些发现表明，前额叶多巴胺释放的增加与在印防己毒素治疗的小鼠中观察到的抗享乐作用有关。
Background and PurposePrefrontal dopamine release by the combined activation of 5‐HT1Aand sigma‐1 (σ1) receptors is enhanced by the GABAAreceptor antagonist picrotoxin in mice. Here, we examined whether this neurochemical event was accompanied by behavioural changes.Experimental ApproachMale mice were treated with picrotoxin to decrease GABAAreceptor function. Their anhedonic behaviour was measured using the female encounter test. The expression of c‐Fos was determined immunohistochemically.Key ResultsPicrotoxin caused an anxiogenic effect on three behavioural tests, but it did not affect the immobility time in the forced swim test. Picrotoxin decreased female preference in the female encounter test and attenuated the female encounter‐induced increase in c‐Fos expression in the nucleus accumbens. Picrotoxin‐induced anhedonia was ameliorated by fluvoxamine andS‐(+)‐fluoxetine, selective serotonin reuptake inhibitors with high affinity for the σ1receptor. The effect of fluvoxamine was blocked by a 5‐HT1Aor a σ1receptor antagonist, and co‐administration of the σ1receptor agonist (+)‐SKF‐10047 and the 5‐HT1Areceptor agonist osemozotan mimicked the effect of fluvoxamine. By contrast, desipramine, duloxetine and paroxetine, which have little affinity for the σ1receptor, did not affect picrotoxin‐induced anhedonia. The effect of fluvoxamine was blocked by a dopamine D2/3receptor antagonist. Methylphenidate, an activator of the prefrontal dopamine system, ameliorated picrotoxin‐induced anhedonia.Conclusion and ImplicationsPicrotoxin‐treated mice show anhedonic behaviour that is ameliorated by simultaneous activation of 5‐HT1Aand σ1receptors. These findings suggest that the increased prefrontal dopamine release is associated with the anti‐anhedonic effect observed in picrotoxin‐treated mice.