Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, 19615-1178, Tehran, Iran.
Neuromolecular Med. 2013 Sep;15(3):523-35. doi: 10.1007/s12017-013-8238-x. Epub 2013 Jun 21.
Behavioral sensitization (B.S.) is a pathophysiological animal model for stimulant-induced psychosis and addiction. Accumulated evidence indicates that inflammatory processes are involved in psychostimulants effects in the CNS. Cannabinoids like WIN55,212-2 act as potential activators of PPAR-γ and affects the inflammatory status of the CNS. The purpose of this study is to determine PPAR-γ role in induction and expression of B.S. and the coincident inflammatory responses developed by WIN55,212-2 (WIN). Using open-field test, locomotor activity was monitored in animals treated with intraperitoneal low-dose WIN single or repeated injections. Concurrent striatal COX-2 and TNF-α levels and PPAR-γ activity were determined by immunoblotting assay. Effects of concomitant chronic or acute PPAR-γ pharmacological inhibition (with GW9662) were then investigated on behavioral and biochemical variables. WIN enhanced locomotor activity and while administered chronically augmented cytosolic COX-2 and TNF-α and also PPAR-γ nuclear levels. GW9662 co-administration completely prevented the induction of sensitizing effects of chronic WIN and altered the inflammatory responses. However, the expression of B.S. was intensified with GW9662 as assessed by increased locomotion after WIN challenge following 48 h withdrawal. Neuroinflammation and locomotor excitability in animals received just a single-dose WIN were also escalated with GW9662. Our findings conclude that PPAR-γ could play different key roles during B.S. development by WIN. Although PPAR-γ is mostly known for neuroprotective and anti-inflammatory effects, our data indicate that it mediates the B.S. induction by chronic WIN. However, while the B.S. was induced, PPAR-γ could play a homeostatic role opposing the expressed B.S. escalation.
行为敏化（B.S.）是一种用于研究兴奋剂引起的精神病和成瘾的病理生理学动物模型。有大量证据表明，炎症过程参与了中枢神经系统中精神兴奋剂的作用。大麻素如 WIN55,212-2 作为 PPAR-γ 的潜在激活剂，影响中枢神经系统的炎症状态。本研究的目的是确定 PPAR-γ 在诱导和表达 B.S.中的作用，以及 WIN55,212-2 (WIN) 引起的炎症反应。通过旷场测试，监测接受腹腔内低剂量 WIN 单次或重复注射的动物的运动活动。通过免疫印迹法测定纹状体 COX-2 和 TNF-α 水平和 PPAR-γ 活性。然后研究了同时进行的慢性或急性 PPAR-γ 药理学抑制（用 GW9662）对行为和生化变量的影响。WIN 增强了运动活动，而慢性给予则增加了胞质 COX-2 和 TNF-α 以及 PPAR-γ 核水平。GW9662 共同给药完全阻止了慢性 WIN 诱导的敏化作用的发生，并改变了炎症反应。然而，GW9662 增加了运动活动，表明 B.S. 的表达在 WIN 挑战后 48 小时戒断后加剧。接受单次剂量 WIN 的动物的神经炎症和运动兴奋性也因 GW9662 而加剧。我们的研究结果表明，PPAR-γ 在 WIN 诱导的 B.S.发展中可能发挥不同的关键作用。尽管 PPAR-γ 主要因其神经保护和抗炎作用而闻名，但我们的数据表明，它介导了慢性 WIN 诱导的 B.S.。然而，当 B.S. 被诱导时，PPAR-γ 可能发挥一种平衡作用，对抗表达的 B.S.加剧。
