The neurotrophic factor pleiotrophin modulates amphetamine-seeking behaviour and amphetamine-induced neurotoxic effects: evidence from pleiotrophin knockout mice
The neurotrophic factor pleiotrophin modulates amphetamine-seeking behaviour and amphetamine-induced neurotoxic effects: evidence from pleiotrophin knockout mice
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DOI：
10.1111/j.1369-1600.2009.00202.x
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发表时间：
2010-10-01
影响因子：
3.4
通讯作者：
Herradon, Gonzalo
中科院分区：
文献类型：
--
作者：
Gramage, Esther;Putelli, Alessia;Herradon, Gonzalo
神经营养因子PTN在多巴胺能神经元的存活和分化中起重要作用，在苯丙胺作用下，伏隔核中PTN表达上调，提示PTN可调节苯丙胺诱导的药理或神经适应性效应。为了验证这一假设，我们研究了苯丙胺对PTN基因缺陷(PTN-/-)和野生型(WT，+/+)小鼠的影响。在条件性研究中，我们发现苯丙胺诱导PTN-/-和WT(+/+)小鼠的条件性位置偏爱。当这些小鼠在5天不注射苯丙胺后被重新评估时，我们发现WT(+/+)小鼠没有表现出苯丙胺寻找行为，而PTN-/-小鼠仍然表现出强烈的寻找毒品行为。在免疫细胞化学研究中，我们发现苯丙胺(10 mg/kg，4次，每2小时)在末次给药4天后，与WT小鼠相比，苯丙胺处理的PTN-/-小鼠纹状体神经胶质纤维酸性蛋白阳性细胞显著增加，提示在没有内源性PTN的情况下，苯丙胺诱导的星形胶质细胞增加。有趣的是，我们在体外研究中发现，PTN(3 MM)可限制苯丙胺(1 MM)诱导的PC12细胞活力丧失，这一作用可能与PTN诱导Akt和ERK1/2磷酸化的能力有关。为了测试这种可能性，我们首次使用了特异性Akt和ERK1/2抑制剂，发现PTN对苯丙胺诱导的PC12细胞毒性的保护作用是通过ERK1/2信号通路介导的。这些数据表明，PTN在限制苯丙胺诱导的神经毒性和奖赏效应方面发挥了重要作用。
Pleiotrophin (PTN), a neurotrophic factor with important roles in survival and differentiation of dopaminergic neurons, is up-regulated in the nucleus accumbens after amphetamine administration suggesting that PTN could modulate amphetamine-induced pharmacological or neuroadaptative effects. To test this hypothesis, we have studied the effects of amphetamine administration in PTN genetically deficient (PTN -/-) and wild type (WT, +/+) mice. In conditioning studies, we found that amphetamine induces conditioned place preference in both PTN -/- and WT (+/+) mice. When these mice were re-evaluated after a 5-day period without amphetamine administration, we found that WT (+/+) mice did not exhibit amphetamine-seeking behaviour, whereas, PTN -/- mice still showed a robust drug-seeking behaviour. In immunohystochemistry studies, we found that amphetamine (10 mg/kg, four times, every 2 hours) causes a significant increase of glial fibrillary acidic protein positive cells in the striatum of amphetamine-treated PTN -/- mice compared with WT mice 4 days after last administration of the drug, suggesting an enhanced amphetamine-induced astrocytosis in the absence of endogenous PTN. Interestingly, we found in concomitant in vitro studies that PTN (3 mu M) limits amphetamine (1 mM)-induced loss of viability of PC12 cell cultures, effect that could be related to the ability of PTN to induce the phosphorylation of Akt and ERK1/2. To test this possibility, we used specific Akt and ERK1/2 inhibitors uncovering for the first time that PTN-induced protective effects against amphetamine-induced toxicity in PC12 cells are mediated by the ERK1/2 signalling pathway. The data suggest an important role of PTN to limit amphetamine-induced neurotoxic and rewarding effects.