Enomoto Takeshi, Floresco Stan B
Department of Psychology and Brain Research Centre, University of British Columbia, 2136 West Mall, Vancouver B.C., Canada V6T 1Z4.
Prog Neuropsychopharmacol Biol Psychiatry. 2009 Jun 15;33(4):668-75. doi: 10.1016/j.pnpbp.2009.03.013. Epub 2009 Mar 21.
Treatment with non-competitive N-methyl-D-aspartate (NMDA) antagonists such as phencyclidine or ketamine have been shown to induce schizophrenia-like psychotic and cognitive symptoms in humans and animals. However, there have been a number of contradictory findings regarding the effects of repeated treatment with these drugs on working memory in experimental animals. We hypothesized that processes dependent on dopamine transmission in the medial prefrontal cortex (PFC) may be more sensitive to disruption following these treatment. We assessed the effects of repeated treatment with ketamine on working memory performance using a delayed spatial win-shift procedure conducted on a radial-arm maze, dependent on a neural circuit linking hippocampal and dopamine inputs to the medial PFC. Rats were trained on the task prior to drug exposure, after which they were subjected to one of two dosing regimes of ketamine (30 mg/kg twice a day for either 5 or 10 days). After a 10 day withdrawal period, they were re-tested on the task for 15 days. Ketamine treatment for 10 days, but not 5 days, increased the number of errors and days to re-achieve the criterion on the delayed task. However, in a separate group of rats, subchronic ketamine treatment (10 days) did not affect performance of the non-delayed random foraging task, dependent on the hippocampus, but not the PFC. These results indicate that working memory performance assessed with these procedures is sensitive to disruption following repeated exposure to ketamine. Impairments in working memory induced by these treatments are not attributable to dysfunction of motivational, motor, short-term or spatial memory processes. The use of these procedures may prove useful in modeling impairments in this executive function observed in schizophrenia.
使用非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂如苯环己哌啶或氯胺酮进行治疗，已被证明会在人类和动物身上诱发类似精神分裂症的精神病性和认知症状。然而，关于这些药物重复治疗对实验动物工作记忆的影响，存在许多相互矛盾的研究结果。我们推测，内侧前额叶皮质（PFC）中依赖多巴胺传递的过程可能对这些治疗后的破坏更为敏感。我们使用在放射状臂迷宫上进行的延迟空间赢移程序，评估了氯胺酮重复治疗对工作记忆表现的影响，该程序依赖于连接海马体和多巴胺输入到内侧PFC的神经回路。大鼠在药物暴露前接受该任务训练，之后接受两种氯胺酮给药方案之一（每天两次，每次30mg/kg，持续5天或10天）。在10天的撤药期后，它们在该任务上重新测试15天。氯胺酮治疗10天而非5天，增加了错误数量以及重新达到延迟任务标准所需的天数。然而，在另一组大鼠中，亚慢性氯胺酮治疗（10天）并未影响依赖海马体而非PFC的非延迟随机觅食任务的表现。这些结果表明，用这些程序评估的工作记忆表现对重复暴露于氯胺酮后的破坏很敏感。这些治疗引起的工作记忆损害并非归因于动机、运动、短期或空间记忆过程的功能障碍。使用这些程序可能有助于模拟在精神分裂症中观察到的这种执行功能损害。
