Prepulse inhibition and prevertion of disease in a putative animal model of schizophrenia

通过神经解剖学或环境操作，大鼠表现出脉冲前抑制(PPI)缺陷。本研究的目的是确定损毁单侧内嗅皮层(EC)和/或隔离住房是否影响青春期大鼠的听性惊厥的PPI。我们还研究了氟哌啶醇或氯氮平对EC损毁大鼠PPI的急性影响。将喹啉酸(损伤手术)或磷酸盐缓冲盐水(假手术)注入青春期(出生后7周)雄性Wistar大鼠一侧EC。术后将大鼠单独或成对安置，形成损伤/隔离、损伤/成对、假/隔离、假/成对4组。术后第28天，与假手术组大鼠相比，单侧损伤组大鼠的PPI明显降低。此外，与左侧病变/隔离大鼠相比，左侧病变/隔离大鼠的PPI值下降更明显，w…然而，在右撇子大鼠中没有发现这种隔离的效果。氟哌啶醇和氯氮平均能逆转左侧或右侧EC损毁大鼠PPI的破坏。这些结果提示，左侧EC损毁可增强环境应激在感觉运动门控中产生紊乱的能力，EC损毁大鼠PPI的破坏可能依赖于多巴胺(DA)传递的改变。此外，我们测量了这些动物的DA相关行为和甲基苯丙胺(MAP)诱导的伏核(NAC)中DA的释放。损伤大鼠在术后第14天和第28天表现出明显的自发或MAP(1 mg/kg，i.p)诱导的运动活动。术后第28天用体内微透析法测定MAP诱导的NAC DA释放。与假手术动物相比，损毁大鼠在MAP诱导的NAC中的DA释放没有明显变化。这些结果提示，兴奋性损伤左侧EC可引起与中脑边缘多巴胺能传递变化一致的行为改变，这种改变可能是由突触后优势所介导的。苯环利定(PCP)治疗的动物被认为是精神分裂症的动物模型。精氨酸加压素(AVP)是一种参与啮齿动物社会行为的多肽。为探讨阻断N-甲基-D-天冬氨酸(NMDA)受体导致大鼠社会行为障碍的机制，本研究观察了PCP对AVP受体结合和社会相互作用的影响。亚慢性五氯苯酚(2 mg/kg/d，14天，i.p)显著降低由[125I]-线性AVP拮抗剂标记的V1a受体结合位点在几个脑区的密度。五氯苯酚的亚慢性治疗损害了大鼠的社会互动，正如先前报道的那样。这些结果提示，NMDA拮抗剂对中枢加压素能系统和社会相互作用有调节作用。较少

Prepulse inhibition(PPI) deficits have been shown in rats through neuroanatomical or environmental manipulation. The aim of this study was to determine whether unilateral entorhinal cortical(EC) lesions and/or isolation-housing influence the PPI of acoustic startle in adolescent rats. We also investigated the acute effects of haloperidol or clozapine on the disruption of PPI in the EC lesioned rats. Quinolinic acid (lesion operation) or phosphate buffered saline (sham operation) was infused into the unilateral EC of adolescent (postnatal 7 weeks) male Wistar rats. After operation, the rats were housed individually or pair-housed, thus yielding lesion/isolation, lesion/pair, sham/isolation, and sham/pair groups. On the 28th postoperative day, the rats with the unilateral lesions exhibited attenuation of PPI compared with that of the sham-operated rats. Moreover, the left lesion/isolation rats demonstrated a significantly greater decrease in PPI compared with the left lesion/pair rats, w … More hile this effect of isolation was not found in the right-lesioned rats. Both haloperidol and clozapine reversed the disruption of PPI in the left or right EC lesioned rats. These findings suggest that left EC lesions may enhance the ability of environmental stress to produce disturbances in sensorimotor gating, and that the disruption of PPI in EC lesioned rats may be dependent on altered dopamine (DA) transmissions. Furthermore, we measured DA-related behaviors and methamphetamine (MAP)-induced DA release in the accumbens (NAC) nucleus in these animals. The lesioned rats exhibited significantly greater spontaneous or MAP (1mg/kg, i.p.)-induced locomotor activity on the 14th and 28th postoperative day. MAP-induced DA release in NAC was measured by in vivo microdialysis on the 28th postoperative day. Lesioned rats did not show a significant change in MAP-induced DA release in NAC compared to sham-operated animals. These results suggest that excitotoxic damage of the left EC produces behavioral changes consistent with alterd mesolimbic dopaminergic transmissions, possibly mediated by postsynaptic supersesitivity.Animals treated with phencyclidine (PCP) are thought animal models of schizophrenia. Arginine vasopressin(AVP) is a peptide involved in social behaviors in rodents. To iinvestigate the mechanism underlying the deficits in social behavior induced by blockade of N-methyl-D-aspartate (NMDA) receptors, this study examined the effect of PCP on AVP receptor binding and social interaction in the rats. Subchronic PCP administration (2mg/kg/day, 14 days, i.p.) significantly reduced the density of V1a reveptor binding sites, labeled by an [125i]-linear AVP antagonist, in several brain regions. Subchronic treatment with PCP impaired social interactions in rats, as has been previously reported. These results suggest that NMDA antagonists have modulatory effects on the central vasopressinergic system and social interaction. Less