Lack of CB1 receptor activity impairs serotonergic negative feedback
Lack of CB1 receptor activity impairs serotonergic negative feedback
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DOI：
10.1111/j.1471-4159.2009.06025.x
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发表时间：
2009-05-01
影响因子：
4.7
通讯作者：
Valverde, Olga
中科院分区：
文献类型：
--
作者：
Aso, Ester;Renoir, Thibault;Valverde, Olga
血清素能系统和内源性大麻素系统是控制情绪行为的重要基础，越来越多的证据表明其参与情绪障碍的病理生理学。在本研究中，CB1 大麻素受体活性的缺失会损害小鼠的血清素负反馈。因此，体内微透析实验表明，与野生型小鼠相比，CB1敲除小鼠的前额皮质中基础5-HT细胞外水平增加，并且氟西汀诱导的5-HT细胞外水平增加减弱。这些观察结果可能与 CB1 敲除小鼠额叶皮层和海马体中检测到的 5-HT 转运蛋白结合位点密度显着降低有关。 CB1受体的缺乏也改变了一些与5-HT反馈相关的5-HT受体。中缝背核 (DRN) 的细胞外记录表明，CB1 受体的遗传和药理学阻断诱导了 5-HT1A 自身受体功能脱敏。原位杂交研究表明，与情绪反应控制相关的几个大脑区域（例如下丘脑的 DRN、伏隔核和室旁核）内 5-HT2C 受体的表达减少，而在腹侧海马的 CA3 区域观察到过度表达。这些结果表明，缺乏 CB1 受体会通过改变 5-HT 反馈的不同组成部分以及小鼠前额皮质细胞外 5-HT 水平的增加，从而促进 DRN 中血清素能神经元的活动。
Serotonergic and endocannabinoid systems are important substrates for the control of emotional behaviour and growing evidence show an involvement in the pathophysiology of mood disorders. In the present study, the absence of the activity of the CB1 cannabinoid receptor impaired serotonergic negative feedback in mice. Thus, in vivo microdialysis experiments revealed increased basal 5-HT extracellular levels and attenuated fluoxetine-induced increase of 5-HT extracellular levels in the prefrontal cortex of CB1 knockout compared with wild-type mice. These observations could be related to the significant reduction in the 5-HT transporter binding site density detected in frontal cortex and hippocampus of CB1 knockout mice. The lack of CB1 receptor also altered some 5-HT receptors related to the 5-HT feedback. Extracellular recordings in the dorsal raphe nucleus (DRN) revealed that the genetic and pharmacological blockade of CB1 receptor induced a 5-HT1A autoreceptor functional desensitization. In situ hybridization studies showed a reduction in the expression of the 5-HT2C receptor within several brain areas related to the control of the emotional responses, such as the DRN, the nucleus accumbens and the paraventricular nucleus of the hypothalamus, whereas an over-expression was observed in the CA3 area of the ventral hippocampus. These results reveal that the lack of CB1 receptor induces a facilitation of the activity of serotonergic neurons in the DRN by altering different components of the 5-HT feedback as well as an increase in 5-HT extracellular levels in the prefrontal cortex in mice.