Pharmacological blockade of either cannabinoid CB1 or CB2 receptors prevents both cocaine-induced conditioned locomotion and cocaine-induced reduction of cell proliferation in the hippocampus of adult male rat.
Pharmacological blockade of either cannabinoid CB1 or CB2 receptors prevents both cocaine-induced conditioned locomotion and cocaine-induced reduction of cell proliferation in the hippocampus of adult male rat.
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DOI：
10.3389/fnint.2013.00106
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发表时间：
2014
影响因子：
3.5
通讯作者：
Rodriguez de Fonseca F
中科院分区：
文献类型：
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作者：
Blanco-Calvo E;Rivera P;Arrabal S;Vargas A;Pavón FJ;Serrano A;Castilla-Ortega E;Galeano P;Rubio L;Suárez J;Rodriguez de Fonseca F
对可卡因等主要滥用药物的成瘾，最近被认为与成人海马体神经发生的改变有关。内源性大麻素系统调节这种增殖反应，发现大麻素CB1和CB2受体的药理激活/阻断不仅调节神经发生，还调节大脑中的细胞死亡。在本研究中，我们评估了内源性大麻素系统是否影响可卡因诱导的细胞增殖改变。为此，我们检测了CB1（利莫那班，3mg /kg）或CB2受体（AM630, 3mg /kg）的药物阻断是否会影响侧脑室室下区（SVZ）和齿状亚颗粒区（SGZ）的细胞增殖[细胞被标记为5-溴-2 ' -脱氧尿苷（BrdU）]。此外，在急性和重复（4天）可卡因给药（20 mg/kg）期间，我们测量了纹状体和海马的细胞凋亡（通过cleaved caspase-3的表达来监测）和胶质细胞活化（通过分析胶质纤维酸性蛋白（GFAP）和Iba-1的表达）。结果表明，急性可卡因暴露减少了SVZ和SGZ中brdu免疫反应（ir）细胞的数量。相反，重复的可卡因暴露只减少了SVZ的BrdU-ir细胞的数量。急性和重复可卡因暴露都增加了海马中断裂的caspase-3-、GFAP-和Iba1-ir细胞的数量，AM630或利莫那班可以抵消这种影响，从而增加海马中BrdU-、GFAP-和Iba1-ir细胞的数量。这些结果表明，通过药物阻断CB1和CB2，反复给药引起的神经源性、凋亡和胶质过程的变化是正常的。大麻素受体阻断对海马细胞增殖的恢复作用与预防条件性运动的诱导有关，但与预防可卡因诱导的致敏性无关。
Addiction to major drugs of abuse, such as cocaine, has recently been linked to alterations in adult neurogenesis in the hippocampus. The endogenous cannabinoid system modulates this proliferative response as demonstrated by the finding that pharmacological activation/blockade of cannabinoid CB1 and CB2 receptors not only modulates neurogenesis but also modulates cell death in the brain. In the present study, we evaluated whether the endogenous cannabinoid system affects cocaine-induced alterations in cell proliferation. To this end, we examined whether pharmacological blockade of either CB1 (Rimonabant, 3 mg/kg) or CB2 receptors (AM630, 3 mg/kg) would affect cell proliferation [the cells were labeled with 5-bromo-2′-deoxyuridine (BrdU)] in the subventricular zone (SVZ) of the lateral ventricle and the dentate subgranular zone (SGZ). Additionally, we measured cell apoptosis (as monitored by the expression of cleaved caspase-3) and glial activation [by analyzing the expression of glial fibrillary acidic protein (GFAP) and Iba-1] in the striatum and hippocampus during acute and repeated (4 days) cocaine administration (20 mg/kg). The results showed that acute cocaine exposure decreased the number of BrdU-immunoreactive (ir) cells in the SVZ and SGZ. In contrast, repeated cocaine exposure reduced the number of BrdU-ir cells only in the SVZ. Both acute and repeated cocaine exposure increased the number of cleaved caspase-3-, GFAP- and Iba1-ir cells in the hippocampus, and this effect was counteracted by AM630 or Rimonabant, which increased the number of BrdU-, GFAP-, and Iba1-ir cells in the hippocampus. These results indicate that the changes in neurogenic, apoptotic and gliotic processes that were produced by repeated cocaine administration were normalized by pharmacological blockade of CB1 and CB2. The restorative effects of cannabinoid receptor blockade on hippocampal cell proliferation were associated with the prevention of the induction of conditioned locomotion but not with the prevention of cocaine-induced sensitization.