慢性氯胺酮（K粉）暴露所致ICR小鼠学习记忆损害及ω-3多不饱和脂肪酸干预效果的氨基酸能机制研究

Chronic ketamine exposure may cause learning, memory and other cognitive disorders,The imaging studies have found that chronic ketamine exposure leads to structure and function impairment in the prefrontal cortex, which may not be restored completely in a short time,and it will likely affect patients'social function for a long time.Currently,there is little informantion is available to indicate accurat biology mechanism of structure and function impairment result from chronic ketamine exposure.Furthermore,research about intervention of ketamine- induced cognitive impairment has not been concerned about .ω-3 polyunsaturated fatty acids (ω-3 PUFAs) improve learning and memory function of Alzheimer's disease patients has been confirmed by a large number of animal and human clinical studies，meanwhile chronic ketamine exposure may leads to some neuropathological changes similar as Alzheimer's disease, so in the present study,we choose amino acid receptors and neurotransmitters, which affected directly by ketamine and closely related with cognitive ,as observed target, and select ω-3 PUFAs as method of intervention.Dynamic process of amino acid neurotransmitters density and expression of receptor gene （and protein） in the PFC and hippocampus will be determined by microdialysis and other molecular biology methods.Through the above means,we hope to get some useful result to interprete the reason of cognitive dyfunction caused by chronic ketamine exposure and to evaluate the possible effects of ω-3 PUFAs on the above cognitive dyfunction.

慢性氯胺酮（K粉）暴露会导致学习、记忆等认知功能损害，影像学研究表明慢性氯胺酮暴露会导致前额叶皮质结构的损害，且这些损害短期无法恢复，长期影响个体的社会功能。目前，慢性氯胺酮暴露改变脑部结构、影响认知功能的确切分子生物学机制仍不清楚，氯胺酮所致认知功能损害的干预和治疗更是一个研究盲区。ω-3 多不饱和脂肪酸能改善阿尔茨海默病患者的学习、记忆功能得到了大量动物及人类临床研究的证实，同时慢性氯胺酮暴露会导致某些与阿尔茨海默病类似的神经病理改变。因此本研究选择氯胺酮直接作用且与认知密切相关的氨基酸类递质和受体作为观测指标，使用ω-3多不饱和脂肪酸对其学习、记忆损害进行干预，采用微透析及分子生物学手段，测定小鼠前额叶及海马区的氨基酸类递质含量的动态变化及相应受体的基因转录和蛋白表达水平，以此探究慢性氯胺酮暴露损害认知功能的相关机制及ω-3 PUFAs对这种认知损害的干预效果。

本研究选择氯胺酮直接作用且与认知密切相关的氨基酸类递质和受体作为观测指标，使用二十二碳六烯酸（DHA）对其学习、记忆损害进行干预，采用高效液相色谱技术测定小鼠前额叶及海马区的氨基酸类递质含量的变化及相应受体的蛋白表达水平，以此探究慢性氯胺酮暴露损害认知功能的相关机制及DHA对这种认知损害的干预效果。结果发现慢性氯胺酮暴露会明显降低ICR小鼠在Morris水迷宫试验和八臂迷宫试验中的空间认知功能，并且这种损害会持续较长的时间。补充DHA的摄入能够在一定程度上改善慢性氯胺酮暴露所致的ICR小鼠的空间认知功能损害，DHA对空间认知功能的改善作用于小鼠海马和前额叶皮质中的GABA的水平呈现正相关性。同时本研究还发现小鼠的空间认知功能水平与海马和前额叶皮质中的谷氨酸含量呈负相关性，与小鼠海马和前额叶皮质中的GABA含量呈正相关性。