Peroxisome proliferator-activated receptor gamma activation relieves expression of behavioral sensitization to methamphetamine in mice
Peroxisome proliferator-activated receptor gamma activation relieves expression of behavioral sensitization to methamphetamine in mice
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DOI：
10.1038/sj.npp.1301213
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发表时间：
2007-05-01
影响因子：
7.6
通讯作者：
Kishioka, Shiroh
中科院分区：
文献类型：
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作者：
Maeda, Takehiko;Kiguchi, Norikazu;Kishioka, Shiroh
过氧化物酶体增殖物激活受体（Peroxisome proliferator-activated receptor，PPAR）是一种配体激活的转录因子，调节脂质代谢和炎症。行为致敏是精神兴奋剂性精神病的实验模型;它是由重复给予精神兴奋剂引起的，最近被认为与大脑炎症有关。我们研究了参与的过氧化物酶体增殖物激活受体γ，过氧化物酶体增殖物激活受体的同种型之一，在发展中的行为敏化甲基苯丙胺（甲基）（1毫克/公斤，皮下注射）的刺激作用的小鼠。METH的重复给药（每天一次，持续5天）增强了METH的自发激活作用，这在停药第7天（试验第12天）通过METH激发再现。在METH给药5天后（试验第5天）和停药第7天（试验第12天），全脑核部分中的蛋白水平和PPARg活性显著增加。吡格列酮和环格列酮（PPARg激动剂; 0.5-5.0 μ g，脑室内（i. c. v.），每天一次）阻止了在停药第7天对METH攻击的行为敏化的表达，但不能阻止在重复施用METH期间发生的敏化。此外，行为敏化的表达量通过用GW 9662（一种PPARg拮抗剂; 0.5-5.0 μ g i. c. v.，每日一次）。通过同时i. c. v.注射9-顺式-视黄酸（1.0 mg）协同促进吡格列酮诱导的行为敏化缓解，9-顺式-视黄酸是类维生素A X受体的激动剂，类维生素A X受体是一种配体激活的核受体，与PPAR形成异二聚体。这些结果表明，PPARg在小鼠对METH的行为敏化的表达中具有显著作用。
Peroxisome proliferator-activated receptor ( PPAR) is a ligand-activated transcriptional factor that regulates lipid metabolism and inflammation. Behavioral sensitization is an experimental model of psychostimulant psychosis; it is elicited by repeated administration of psychostimulants and has recently been implicated in brain inflammation. We examined the involvement of PPAR gamma, one of the isotypes of PPAR, in development of behavioral sensitization to the stimulant effect of methamphetamine ( METH) (1 mg/kg, subcutaneously) in mice. Repeated administration of METH ( once daily for 5 days) enhanced the locomotor-activating effect of METH, which was reproduced by METH challenge on withdrawal day 7 ( test day 12). The protein level and the activity of PPARg were significantly increased in the nuclear fraction of whole brain after 5 days of METH administration ( test day 5) and on withdrawal day 7 ( test day 12). Both pioglitazone and ciglitazone ( PPARg agonists; 0.5-5.0 mu g, intracerebroventricularly (i.c.v.), once daily) prevented the expression of behavioral sensitization to METH challenge on withdrawal day 7, but not the sensitization that occurred during repeated administration of METH. In addition, the magnitude of expression of behavioral sensitization was augmented by treatments with GW9662 ( a PPARg antagonist; 0.5-5.0 mu g i.c.v., once daily) during the withdrawal period. The pioglitazone-induced alleviation of behavioral sensitization was synergistically facilitated by simultaneous i.c.v. injection of 9-cis-retinoic acid (1.0 mg), an agonist for the retinoid X receptor which is a ligand-activated nuclear receptor that forms heterodimers with PPAR. These results suggest that PPARg has a significant role in the expression of behavioral sensitization to METH in mice.