Saint Marie Richard L, Neary Alaina C, Shoemaker Jody M, Swerdlow Neal R
Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, CA 92103-0804, USA.
Brain Res. 2006 Nov 13;1119(1):203-14. doi: 10.1016/j.brainres.2006.08.045. Epub 2006 Sep 18.
We previously reported that Sprague-Dawley (SD) rats are significantly more sensitive than Long Evans (LE) rats to disruption of prepulse inhibition (PPI) of the startle reflex by the dopamine agonists, apomorphine (APO) and D-amphetamine (AMPH). This susceptibility is inherited through F1 (SD x LE) and N2 backcross (F1 x SD) generations via an orderly pattern (SD>N2>F1>LE). Here we examined systemic APO (0.5 mg/kg) and AMPH (4.5 mg/kg) modulation of neural activity in four regions of the striatum suspected to be involved in the dopaminergic regulation of PPI - dorsolateral (dlCPu) and medial (mCPu) caudate/putamen and core (NACc) and medial shell (NACms) regions of nucleus accumbens - under conditions that mimicked those used to assess PPI. Immunohistochemical quantification of c-Fos protein expression was used as the surrogate measure of neural activity in SD and LE rats and their F1 crosses. Vehicle-treatment showed significant regional differences in Fos expression, particularly between the dlCPu and the other three areas, but no strain-related differences were observed. Three of four brain areas examined (dlCPu, mCPu and NACc) exhibited drug-induced changes in Fos expression--APO decreased and AMPH increased Fos expression in each region. The aggregate effect across these three regions revealed Fos expression to be significantly greater in LE compared to SD rats for both drugs, with F1 rats intermediate. This pattern of inheritance (LE>F1>SD) reveals an inverse relationship between striatal Fos expression and PPI sensitivity for these drugs; and a positive relationship with reported heritable differences in D2-linked G-protein binding in the CPu and NACc, and with locomotor activation/suppression by AMPH and APO.
我们之前报道过，与长 Evans（LE）大鼠相比，斯普拉格-道利（SD）大鼠对多巴胺激动剂阿扑吗啡（APO）和 D-苯丙胺（AMPH）破坏惊吓反射的前脉冲抑制（PPI）更为敏感。这种易感性通过 F1（SD×LE）和 N2 回交（F1×SD）代以一种有序模式遗传（SD＞N2＞F1＞LE）。在此，我们在模拟用于评估 PPI 的条件下，研究了全身给予 APO（0.5 毫克/千克）和 AMPH（4.5 毫克/千克）对纹状体四个区域神经活动的调节作用，这四个区域被怀疑参与 PPI 的多巴胺能调节——背外侧（dlCPu）和内侧（mCPu）尾状核/壳核以及伏隔核的核心（NACc）和内侧壳（NACms）区域。采用免疫组织化学定量 c-Fos 蛋白表达作为 SD 和 LE 大鼠及其 F1 杂交后代神经活动的替代指标。给予溶剂对照处理时，Fos 表达存在显著的区域差异，特别是在 dlCPu 与其他三个区域之间，但未观察到品系相关差异。所检测的四个脑区中的三个（dlCPu、mCPu 和 NACc）表现出药物诱导的 Fos 表达变化——APO 使每个区域的 Fos 表达降低，而 AMPH 使其增加。这三个区域的总体效应显示，对于两种药物，LE 大鼠的 Fos 表达均显著高于 SD 大鼠，F1 大鼠介于两者之间。这种遗传模式（LE＞F1＞SD）揭示了纹状体 Fos 表达与这些药物的 PPI 敏感性之间呈负相关；并且与报道的 CPu 和 NACc 中 D2 连接的 G 蛋白结合的遗传差异以及 AMPH 和 APO 对运动的激活/抑制呈正相关。
