Murray Ryan C, Gilbert Yamiece E, Logan Anna S, Hebbard John C, Horner Kristen A
Division of Basic Medical Sciences, Mercer University School of Medicine, 1550 College St., Macon, GA, 31207, USA.
Brain Struct Funct. 2014 Jul;219(4):1213-29. doi: 10.1007/s00429-013-0559-x. Epub 2013 Apr 27.
Methamphetamine (METH) induces stereotypy, which is characterized as inflexible, repetitive behavior. Enhanced activation of the patch compartment of the striatum has been correlated with stereotypy, suggesting that stereotypy may be related to preferential activation of this region. However, the specific contribution of the patch compartment to METH-induced stereotypy is not clear. To elucidate the involvement of the patch compartment to the development of METH-induced stereotypy, we determined if destruction of this sub-region altered METH-induced behaviors. Animals were bilaterally infused in the striatum with the neurotoxin dermorphin-saporin (DERM-SAP; 17 ng/μl) to specifically ablate the neurons of the patch compartment. Eight days later, animals were treated with METH (7.5 mg/kg), placed in activity chambers, observed for 2 h and killed. DERM-SAP pretreatment significantly reduced the number and total area of mu-labeled patches in the striatum. DERM-SAP pretreatment significantly reduced the intensity of METH-induced stereotypy and the spatial immobility typically observed with METH-induced stereotypy. In support of this observation, DERM-SAP pretreatment also significantly increased locomotor activity in METH-treated animals. In the striatum, DERM-SAP pretreatment attenuated METH-induced c-Fos expression in the patch compartment, while enhancing METH-induced c-Fos expression in the matrix compartment. DERM-SAP pretreatment followed by METH administration augmented c-Fos expression in the SNpc and reduced METH-induced c-Fos expression in the SNpr. In the medial prefrontal, but not sensorimotor cortex, c-Fos and zif/268 expression was increased following METH treatment in animals pre-treated with DERM-SAP. These data indicate that the patch compartment is necessary for the expression of repetitive behaviors and suggests that alterations in activity in the basal ganglia may contribute to this phenomenon.
甲基苯丙胺（METH）会诱发刻板行为，其特征为僵化、重复的行为。纹状体斑块区的激活增强与刻板行为相关，这表明刻板行为可能与该区域的优先激活有关。然而，斑块区对METH诱发的刻板行为的具体作用尚不清楚。为了阐明斑块区在METH诱发的刻板行为发展中的作用，我们确定该亚区域的破坏是否会改变METH诱发的行为。向动物双侧纹状体内注射神经毒素皮啡肽-皂草素（DERM-SAP；17 ng/μl），以特异性消融斑块区的神经元。八天后，给动物注射METH（7.5 mg/kg），放入活动箱中，观察2小时后处死。DERM-SAP预处理显著减少了纹状体中μ标记斑块的数量和总面积。DERM-SAP预处理显著降低了METH诱发的刻板行为的强度以及METH诱发的刻板行为中通常观察到的空间不动性。支持这一观察结果的是，DERM-SAP预处理还显著增加了METH处理动物的运动活性。在纹状体中，DERM-SAP预处理减弱了METH诱发的斑块区c-Fos表达，同时增强了METH诱发的基质区c-Fos表达。DERM-SAP预处理后给予METH增加了黑质致密部（SNpc）的c-Fos表达，并降低了METH诱发的黑质网状部（SNpr）的c-Fos表达。在内侧前额叶而非感觉运动皮层中，DERM-SAP预处理动物在METH处理后c-Fos和zif/268表达增加。这些数据表明，斑块区对于重复行为的表达是必要的，并表明基底神经节活动的改变可能导致了这一现象。
