Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice
Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice
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DOI：
10.1124/mol.66.2.204
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发表时间：
2004-08-01
影响因子：
3.6
通讯作者：
Greenberg, DA
中科院分区：
文献类型：
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作者：
Jin, KL;Xie, L;Greenberg, DA
药理学研究表明CB 1大麻素受体（CB 1 R）在调节成人大脑神经发生中的作用。为了研究这种可能性，我们通过腹膜内注射标记新生神经元的溴脱氧尿苷（BrdU），在野生型和CB 1 R基因敲除（CB 1 R-KO）小鼠中测量神经发生。CB 1 R-KO小鼠齿状回和脑室下区（SVZ）BrdU标记细胞数量减少至野生型（WT）水平的50%，表明CB 1 R激活促进神经发生。为了进一步测试这一点，在用BrdU测量神经发生之前，给予WT小鼠CB 1 R拮抗剂N-（哌啶-1-基）-5-（4-氯苯基）-1-（2，4-二氯苯基）-4-甲基-1H-吡唑-3-甲酰胺盐酸盐（SR 141716 A）。SR 141716 A使SVZ中BrdU标记细胞的数量增加了50%;另一种CB 1 R拮抗剂1-（2，4-二氯苯基）-5-（4-碘苯基）-4-甲基-N-1-哌啶基-1H-吡唑-3-甲酰胺（AM 251）具有相似的作用。为了研究这种差异，将SR 141716 A给予CB 1 R-KO小鼠，在小鼠中它仍然刺激神经发生，表明涉及非CB 1受体。通过将SR 141716 A给予VR 1-KO小鼠，检测了对一个非CB 1（SR 141716 A敏感位点，即VR 1香草素受体）的作用，其中SR 141716 A增强神经发生的能力被消除。因此，CB 1和VR 1受体似乎都在调节成人神经发生中发挥作用。
Pharmacological studies suggest a role for CB1 cannabinoid receptors (CB1R) in regulating neurogenesis in the adult brain. To investigate this possibility, we measured neurogenesis by intraperitoneal injection of bromodeoxyuridine ( BrdU), which labels newborn neurons, in wild-type and CB1R-knockout (CB1R-KO) mice. CB1R-KO mice showed reductions in the number of BrdU-labeled cells to similar to50% of wild-type (WT) levels in dentate gyrus and subventricular zone (SVZ), suggesting that CB1R activation promotes neurogenesis. To test this further, WT mice were given the CB1R antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A) before measuring neurogenesis with BrdU. SR141716A paradoxically increased the number of BrdU-labeled cells by similar to50% in SVZ; another CB1R antagonist, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251), had a similar effect. To investigate this discrepancy, SR141716A was given to CB1R-KO mice, in which it still stimulated neurogenesis, indicating involvement of a non-CB1 receptor. Action at one such non-CB1, SR141716A-sensitive site, the VR1 vanilloid receptor, was tested by administering SR141716A to VR1-KO mice, in which the ability of SR141716A to enhance neurogenesis was abolished. Thus, CB1 and VR1 receptors both seem to have roles in regulating adult neurogenesis.