Department of Psychological and Brain Sciences, University of California, Santa Barbara, CA 93106-9660, USA.
Department of Physics, University of California, Santa Barbara, CA 93106-9660, USA.
Pharmacol Biochem Behav. 2019 Apr;179:150-155. doi: 10.1016/j.pbb.2019.01.003. Epub 2019 Jan 16.
Bipolar illness is characterized by periods of "mania" - high energy, irritability, and increased psychomotor activation. While the neurobiological investigation of mania has been limited by the lack of reliable animal models, researchers have recently reported that daily subanesthetic doses of ketamine produce a lithium-reversible increase in rodent locomotor activity. Such studies have typically employed short-term (2 week) exposure to daily intraperitoneal-injected lithium and extremely brief (i.e., 5-min) open-field tests of hyperactivity. To increase the translational utility of the model, the effects of 70-days of orally administered lithium were examined on ketamine-induced hyperlocomotion during 30-min test sessions. Rats consumed 2.0 mEq/kg lithium chloride (LiCl) presented daily in a high incentive food (10 g of peanut butter). Control animals ingested peanut butter infused with an equimolar concentration of sodium chloride (NaCl). After 60 days of treatment, a 30-min baseline revealed no differences in the locomotor activity of LiCl and NaCl animals. During the next 10 days, animals received single daily supplemental injections of 25 mg/kg IP ketamine. A subset of animals was injected daily with saline and served as non-ketamine controls. Behavioral testing on the final two days of treatment confirmed that ketamine administration produced a profound increase in locomotor activity that was significantly attenuated in the LiCl group. Additionally, blood plasma levels of lithium were found to be comparable to low-moderate human therapeutic levels. These data confirm the viability and utility of ketamine-induced hyperlocomotion as a rodent model of mania.
双相情感障碍的特征是“躁狂”期——精力旺盛、易怒和精神运动激活增加。虽然对躁狂症的神经生物学研究受到缺乏可靠动物模型的限制，但研究人员最近报告称，每日亚麻醉剂量的氯胺酮会导致啮齿动物运动活动增加，这种增加可被锂逆转。此类研究通常采用短期（2 周）腹腔内注射锂暴露和极短（即 5 分钟）的过度活跃开放场测试。为了增加该模型的转化实用性，研究了 70 天口服给予锂对 30 分钟测试期间氯胺酮诱导的过度活跃的影响。大鼠每天摄入 2.0 mEq/kg 的氯化锂（LiCl），以高激励食物（10 克花生酱）呈现。对照动物摄入含有等摩尔浓度氯化钠（NaCl）的花生酱。治疗 60 天后，30 分钟的基线显示 LiCl 和 NaCl 动物的运动活动没有差异。在接下来的 10 天内，动物接受每日一次 25 mg/kg IP 氯胺酮的补充注射。一部分动物每天接受盐水注射，作为非氯胺酮对照。在治疗的最后两天进行行为测试证实，氯胺酮给药导致运动活动显著增加，而 LiCl 组的这种增加明显减弱。此外，发现血浆锂水平与低中度人类治疗水平相当。这些数据证实了氯胺酮诱导的过度活跃作为躁狂症啮齿动物模型的可行性和实用性。
