Howe William M, Tierney Patrick L, Young Damon A, Oomen Charlotte, Kozak Rouba
Neuroscience Research Unit, Pfizer Inc., 610 Main Street, Cambridge, MA, 02139, USA.
Department of Cognitive Neuroscience, Donders Institute, Radboud University Medical Center, Nijmegen, The Netherlands.
Psychopharmacology (Berl). 2015 Nov;232(21-22):4113-27. doi: 10.1007/s00213-015-3955-5. Epub 2015 May 12.
Gestational day 17 methylazoxymethanol (MAM) treatment has been shown to reproduce, in rodents, some of the alterations in cortical and mesolimbic circuitries thought to contribute to schizophrenia.
We characterized the behavior of MAM animals in tasks dependent on these circuitries to see what behavioral aspects of schizophrenia the model captures. We then characterized the integrity of mesolimbic dopamine neurotransmission in a subset of animals used in the behavioral experiments.
MAM animals' capacity for working memory, attention, and resilience to distraction was tested with two different paradigms. Cue-reward learning and motivation were assayed with Pavlovian conditioned approach. Measurements of electrically stimulated phasic and tonic DA release in the nucleus accumbens with fast-scan cyclic voltammetry were obtained from the same animals used in the Pavlovian task.
MAM animals' basic attentional capacities were intact. MAM animals took longer to acquire the working memory task, but once learned, performed at the same level as shams. MAM animals were also slower to develop a Pavlovian conditioned response, but otherwise no different from controls. These same animals showed alterations in terminal DA release that were unmasked by an amphetamine challenge.
The predominant behavioral-cognitive feature of the MAM model is a learning impairment that is evident in acquisition of executive function tasks as well as basic Pavlovian associations. MAM animals also have dysregulated terminal DA release, and this may contribute to observed behavioral differences. The MAM model captures some functional impairments of schizophrenia, particularly those related to acquisition of goal-directed behavior.
妊娠第17天给予甲基氧化偶氮甲醇（MAM）处理已被证明，在啮齿动物中可重现一些被认为与精神分裂症有关的皮质和中脑边缘回路改变。
我们对接受MAM处理的动物在依赖这些回路的任务中的行为进行了表征，以了解该模型捕捉到了精神分裂症的哪些行为方面。然后，我们对行为实验中一部分动物的中脑边缘多巴胺神经传递的完整性进行了表征。
用两种不同的范式测试了接受MAM处理的动物的工作记忆、注意力和抗干扰能力。用巴甫洛夫条件性接近法测定线索奖励学习和动机。通过快速扫描循环伏安法测量伏隔核中电刺激诱发的相位性和持续性多巴胺释放，这些测量来自巴甫洛夫任务中使用的相同动物。
接受MAM处理的动物的基本注意力能力完好无损。接受MAM处理的动物完成工作记忆任务所需时间更长，但一旦学会，表现与假手术动物相同。接受MAM处理的动物形成巴甫洛夫条件性反应也较慢，但在其他方面与对照组无差异。这些相同的动物在安非他明激发下显示出终末多巴胺释放的改变。
MAM模型的主要行为认知特征是学习障碍，这在执行功能任务以及基本巴甫洛夫联想的习得中很明显。接受MAM处理的动物还存在终末多巴胺释放失调的情况，这可能导致观察到的行为差异。MAM模型捕捉到了精神分裂症的一些功能损害，特别是那些与目标导向行为习得相关的损害。
