Schumacher Anett, Sivanandan Brindan, Tolledo Edgor Cole, Woldegabriel Jacob, Ito Rutsuko
Department of Psychology (Scarborough), University of Toronto, Canada.
Department of Psychology (Scarborough), University of Toronto, Canada; Department of Cell and Systems Biology, University of Toronto, Canada.
Prog Neuropsychopharmacol Biol Psychiatry. 2016 Aug 1;69:1-10. doi: 10.1016/j.pnpbp.2016.03.007. Epub 2016 Apr 8.
Repeated exposure to sub-anesthetic doses of ketamine in rats has been shown to induce cognitive deficits, as well as behavioral changes akin to the negative symptoms of schizophrenia, giving much face validity to the use of ketamine administration as a pharmacological model of schizophrenia. This study sought to further characterize the behavioral effects of two different ketamine pre-treatment regimens, focusing primarily on the effects of repeated ketamine administration on novelty processing, a capacity that is disrupted in schizophrenia. Rats received 5 or 14 intra-peritoneal injections of 30mg/kg ketamine or saline across 5 or 7days, respectively. They were then tested in an associative mismatch detection task to examine their ability to detect novel configurations of familiar audio-visual sequences. Furthermore, rats underwent a sequential novel object and novel object location exploration task. Subsequently, rats were also tested on the delayed matching to place T-maze task, sucrose preference task and locomotor tests involving administering a challenge dose of amphetamine (AMPH). The high-dose ketamine pre-treatment regimen elicited impairments in mismatch detection and working memory. In contrast, the low-dose ketamine pre-treatment regimen improved performance of novelty detection. In addition, low-dose ketamine pre-treated rats showed locomotor sensitization following an AMPH challenge, while the high-dose ketamine pre-treated rats showed an attenuated locomotor response to AMPH, compared to control rats. These findings demonstrate that different regimens of repeated ketamine administration induce alterations in novelty processing in opposite directions, and that differential neural adaptations occurring in the mesolimbic dopamine system may underlie these effects.
研究表明，大鼠反复接受亚麻醉剂量的氯胺酮会导致认知缺陷，以及出现类似于精神分裂症阴性症状的行为变化，这使得氯胺酮给药作为精神分裂症的药理学模型具有很高的表面效度。本研究旨在进一步描述两种不同氯胺酮预处理方案的行为效应，主要关注反复给予氯胺酮对新奇性加工的影响，新奇性加工能力在精神分裂症中会受到破坏。大鼠分别在5天或7天内接受5次或14次腹腔注射30mg/kg氯胺酮或生理盐水。然后，它们接受联想失配检测任务测试，以检查其检测熟悉视听序列新配置的能力。此外，大鼠还进行了连续新奇物体和新奇物体位置探索任务。随后，大鼠还接受了延迟位置匹配T迷宫任务、蔗糖偏好任务以及涉及给予苯丙胺（AMPH）激发剂量的运动测试。高剂量氯胺酮预处理方案导致失配检测和工作记忆受损。相比之下，低剂量氯胺酮预处理方案提高了新奇性检测的表现。此外，与对照大鼠相比，低剂量氯胺酮预处理的大鼠在接受AMPH激发后表现出运动致敏，而高剂量氯胺酮预处理的大鼠对AMPH的运动反应减弱。这些发现表明，不同的反复氯胺酮给药方案会在相反方向上诱导新奇性加工的改变，并且中脑边缘多巴胺系统中发生的不同神经适应可能是这些效应的基础。
