POSTPUBERTAL EMERGENCE OF HYPERRESPONSIVENESS TO STRESS AND TO AMPHETAMINE AFTER NEONATAL EXCITOTOXIC HIPPOCAMPAL DAMAGE - A POTENTIAL ANIMAL-MODEL OF SCHIZOPHRENIA
POSTPUBERTAL EMERGENCE OF HYPERRESPONSIVENESS TO STRESS AND TO AMPHETAMINE AFTER NEONATAL EXCITOTOXIC HIPPOCAMPAL DAMAGE - A POTENTIAL ANIMAL-MODEL OF SCHIZOPHRENIA
复制标题
DOI：
10.1038/npp.1993.44
复制
发表时间：
1993-08-01
影响因子：
7.6
通讯作者：
WEINBERGER, DR
中科院分区：
文献类型：
--
作者：
LIPSKA, BK;JASKIW, GE;WEINBERGER, DR
与精神分裂症相关的主要现象的星座（例如，青春期后发病、先天性海马区损伤、皮质功能缺陷、边缘多巴胺（DA）失调和易受应激性）已经难以用单一的动物模型来解释。虽然它已被证明，大鼠发展增加中脑边缘DA传输和减少皮质DA营业额成年兴奋性毒性病变的腹侧海马（VH），早期发育VH病变的含义是未知的。为了确定这种变化的发展后遗症，我们在出生后第7天（PD 7）的大鼠腹侧海马结构产生鹅膏蕈氨酸病变。运动活动在一个新的环境中，生理盐水注射后，D-安非他明给药后，在PD 35的控制和病变大鼠相似。然而，在成年早期，在PD 56，海马损伤的动物在这些条件下都是过度活跃的。氟哌啶醇预处理可预防PD 56时多动的出现。此外，与成年动物中诱导的类似病变相反，新生大鼠病变对游泳试验评价的应激也反应过度。后一种效应类似于成年后内侧前额叶皮质病变，而不是成年后VH病变，这表明新生儿VH病变可能会影响内侧前额叶皮质的功能发育。这些结果表明，在大鼠与adminatally诱导的兴奋性VH病变，行为指标符合增加中脑边缘DA反应的压力和药理学刺激只出现在成年早期。精神分裂症的病理生理学的某些方面可能是由同源性机制引起的。
The constellation of major phenomena associated with schizophrenia (e.g., postpubertal onset, congenital hippocampal area damage, cortical functional deficits, limbic dopamine (DA) dysregulation, and vulnerability to stress) have been difficult to explain with a unitary animal model. Although it has been shown that rats develop increased mesolimbic DA transmission and reduced cortical DA turnover following adult excitotoxic lesions of the ventral hippocampus (VH), the implication of early developmental VH lesions are not known. To determine the developmental sequelae of such changes, we produced ibotenic acid lesions of the ventral hippocampal formation in rats on the 7th day after birth (PD7). Motor activity in a novel environment, after saline injection and after d-amphetamine administration were similar in control and lesioned rats at PD35. However, in early adulthood, at PD56, animals with the hippocampal lesion were hyperactive in each of these conditions. The emergence of the hyperactivity at PD56 could be prevented by pretreatment with haloperidol. Moreover, rats lesioned as neonates, in contrast to a similar lesion induced in adult animals, were also hyperresponsive to stress evaluated with a swim test. This latter effect is analogous to that seen after adult lesions of the medial prefrontal cortex, rather than after adult lesions of VH, suggesting that the neonatal VH lesion may affect functional development of the medial prefrontal cortex. These results demonstrate that in rats with neonatally induced excitotoxic VH lesions, behavioral indices consistent with increased mesolimbic DA responsivity to stressful and to pharmacologic stimuli emerge only in early adulthood. Homologous mechanisms may underlie certain aspects of the pathophysiology of schizophrenia.