George Sophie A, Rodriguez-Santiago Mariana, Riley John, Abelson James L, Floresco Stan B, Liberzon Israel
Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI, USA; Department of Social and Behavioral Sciences, Dixie State University, 225 South University Ave. E, St George, UT, 84770, USA.
Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI, USA.
Behav Brain Res. 2018 Jul 16;347:332-338. doi: 10.1016/j.bbr.2018.03.037. Epub 2018 Mar 23.
Many psychiatric disorders are associated with cognitive dysfunction that is ineffectively treated by existing pharmacotherapies and which may contribute to poor real-world functioning. D-cycloserine (DCS) is a partial N-methyl-D-aspartate (NMDA) agonist that has attracted attention because of its cognitive enhancing properties, including in people with post-traumatic stress disorder (PTSD). Here, we examined the effect of DCS on reversal learning - a type of cognitive flexibility - following exposure to single prolonged stress (SPS), a rodent model of PTSD. Male Sprague Dawley rats (n = 64) were trained to press levers in an operant chamber, matched for performance and assigned to SPS or control (unstressed) groups. Following SPS, rats received three additional lever press sessions, followed by a side bias test on day three. One day later they learned a response discrimination rule (press left or right lever, opposite to side bias) and on a subsequent day were trained (and tested) for reversal to the opposite lever. DCS (15 mg/kg) or vehicle was administered 30 minutes prior to the reversal session. No between-group differences were found in acquisition or retrieval of the initial rule, but a significant drug x stress interaction on response discrimination reversal indicated that DCS had a greater beneficial effect on SPS rats' cognitive flexibility than it did on performance in controls. These findings add to a growing literature on the beneficial effects of DCS for treating a wide variety of deficits that develop following exposure to extreme stress and may have implications for the development of novel pharmacotherapies for PTSD.
许多精神疾病都与认知功能障碍有关，而现有的药物疗法对这种障碍的治疗效果不佳，且认知功能障碍可能导致现实世界中的功能受损。D-环丝氨酸（DCS）是一种部分N-甲基-D-天冬氨酸（NMDA）受体激动剂，因其具有认知增强特性而受到关注，包括对创伤后应激障碍（PTSD）患者。在此，我们研究了DCS对单次长时间应激（SPS）（一种PTSD的啮齿动物模型）后逆向学习（一种认知灵活性）的影响。雄性Sprague Dawley大鼠（n = 64）在操作箱中接受按压杠杆训练，根据表现进行匹配并分为SPS组或对照组（无应激）。SPS后，大鼠接受另外三次杠杆按压训练，然后在第三天进行侧偏测试。一天后，它们学习一种反应辨别规则（按压左或右杠杆，与侧偏方向相反），并在随后一天接受逆向至相反杠杆的训练（和测试）。在逆向训练前30分钟给予DCS（15 mg/kg）或赋形剂。在初始规则的习得或提取方面未发现组间差异，但在反应辨别逆向方面存在显著的药物×应激交互作用，表明DCS对SPS大鼠认知灵活性的有益影响比对对照组表现的影响更大。这些发现进一步丰富了关于DCS对治疗暴露于极端应激后出现的各种缺陷有益作用的文献，并可能对开发PTSD的新型药物疗法具有启示意义。
