Howland John G, Hannesson Darren K, Phillips Anthony G
Department of Psychology and the Brain Research Centre, University of British Columbia, Vancouver, Canada.
Eur J Neurosci. 2004 Nov;20(10):2639-48. doi: 10.1111/j.1460-9568.2004.03731.x.
Abnormal activity in corticolimbic circuits during development may be a predisposing factor for schizophrenia. Permanent or temporary lesions of limbic structures such as the ventral hippocampus and basolateral amygdala in rats on postnatal day (PND) 7 result in functional changes similar to some behavioural and cognitive signs of schizophrenia. The present experiments tested whether transient increases in the neural activity of corticolimbic circuits on PND 7 would result in similar behavioural changes. Long-Evans rats were treated with either kainic acid (KA, 1.5 mg/kg, i.p.) or saline on PND 7 and tested for prepulse inhibition (PPI) of the acoustic startle response and spontaneous locomotor activity both in a novel environment and following amphetamine treatment before puberty (PND 35) and in early adulthood (PND 56). In subgroups of animals PPI was also measured following apomorphine administration (0.2 mg/kg) and spatial learning and memory were tested in the water maze. Rats treated with KA were indistinguishable from saline-treated animals on PND 35. However, on PND 56, KA-treated animals showed a subtle consistent decrease in PPI relative to control animals, but did not show increased sensitivity to the disruptive effects of a low dose of apomorphine on PPI. Locomotor responses to novelty or amphetamine were not reliably altered in the KA-treated animals. KA- and saline-treated animals performed similarly in the water maze. These results support the hypothesis that neural hyperactivity on PND 7 in rats causes behavioural changes in early adulthood that resemble some symptoms of schizophrenia. These pharmacological data suggest that the changes are not mediated by postsynaptic alterations in mesolimbic dopamine transmission.
发育过程中皮质边缘回路的异常活动可能是精神分裂症的一个易感因素。在出生后第7天（PND 7）对大鼠的边缘结构（如腹侧海马体和基底外侧杏仁核）进行永久性或暂时性损伤，会导致类似于精神分裂症某些行为和认知症状的功能变化。本实验测试了PND 7时皮质边缘回路神经活动的短暂增加是否会导致类似的行为变化。在PND 7给Long-Evans大鼠腹腔注射海人酸（KA，1.5 mg/kg）或生理盐水，并在新环境中以及青春期前（PND 35）和成年早期（PND 56）给予苯丙胺治疗后，测试听觉惊吓反应的前脉冲抑制（PPI）和自发运动活动。在动物亚组中，还在给予阿扑吗啡（0.2 mg/kg）后测量PPI，并在水迷宫中测试空间学习和记忆。在PND 35时，用KA处理的大鼠与用生理盐水处理的动物没有区别。然而，在PND 56时，与对照动物相比，用KA处理的动物PPI出现了轻微但持续的下降，但对低剂量阿扑吗啡对PPI的破坏作用没有表现出更高的敏感性。用KA处理的动物对新奇或苯丙胺的运动反应没有可靠改变。用KA和生理盐水处理的动物在水迷宫中的表现相似。这些结果支持了这样的假设，即大鼠在PND 7时的神经活动亢进会导致成年早期出现类似于精神分裂症某些症状的行为变化。这些药理学数据表明，这些变化不是由中脑边缘多巴胺传递的突触后改变介导的。
