Department of Psychological and Brain Sciences, University of California, Santa Barbara, CA 93106, USA.
Department of Psychological and Brain Sciences, University of California, Santa Barbara, CA 93106, USA.
Pharmacol Biochem Behav. 2020 Mar;190:172875. doi: 10.1016/j.pbb.2020.172875. Epub 2020 Feb 19.
Sub-anesthetic doses of ketamine produce an increase in rodent ambulation that is attenuated by co-administration of naturally-occurring lithium (LiN), the drug most commonly employed in the treatment of bipolar illness. As a consequence, ketamine-induced hyperactivity has been proposed as an animal model of manic behavior. The current study employed a modified version of this model to compare the potency of LiN to that of each of its two stable isotopes - lithium-6 (Li-6) and lithium-7 (Li-7). Since Li-7 constitutes 92.4% of the parent compound it was hypothesized to produce comparable behavioral effects to that of LiN. The current study was devised to determine whether Li-6 might be more, less, or equally effective at tempering hyperactivity relative to Li-7 or to LiN in an animal model of manic behavior. Male rats were maintained on a restricted but high-incentive diet containing a daily dose of 2.0 mEq/kg of lithium (LiN), Li-6 or Li-7 for 30 days. A control group consumed a diet infused with sodium chloride (NaCl) in place of lithium to control for the salty taste of the food. On day 30, baseline testing revealed no differences in the locomotor behavior among the four treatment groups. Animals then continued their Li/NaCl diets for an additional 11 days during which every subject received a single IP injection of either ketamine (25 mg/kg) or 0.9% physiological saline. On the final four days of this regimen, locomotor activity was assessed during 60 min sessions each beginning immediately after ketamine injection. While all three lithium groups produced comparable decreases in ketamine-induced hyperactivity on the first trial, by the fourth trial Li-6 animals exhibited significantly greater and more prolonged reductions in hyperactivity compared to either Li-7 and Li. These results suggest that Li-6 may be more effective at treating mania than its parent compound.
亚麻醉剂量的氯胺酮会增加啮齿动物的活动，而同时给予天然存在的锂（LiN），即最常用于治疗双相情感障碍的药物，则可以减轻这种作用。因此，氯胺酮诱导的过度活动已被提议作为躁狂行为的动物模型。本研究采用了该模型的一种改良版本，比较了 LiN 与其两种稳定同位素（Li-6 和 Li-7）的效力。由于 Li-7 构成了母体化合物的 92.4%，因此假设它会产生与 LiN 相当的行为效应。本研究旨在确定 Li-6 是否相对于 Li-7 或 LiN 在躁狂行为的动物模型中更能、更少或等效地调节过度活动。雄性大鼠被维持在一种限制但高激励的饮食中，其中含有每天 2.0 mEq/kg 的锂（LiN）、Li-6 或 Li-7，持续 30 天。对照组则摄入含有氯化钠（NaCl）的饮食，以控制食物的咸味。第 30 天，基线测试显示四个治疗组之间的运动行为没有差异。然后，动物继续他们的 Li/NaCl 饮食，再额外 11 天，在此期间每个动物都接受单次腹腔注射氯胺酮（25 mg/kg）或 0.9%生理盐水。在该方案的最后四天，在开始注射氯胺酮后立即进行 60 分钟的运动活动评估。虽然所有三种锂组在第一次试验中都产生了类似的降低氯胺酮诱导的过度活动的作用，但在第四次试验中，Li-6 动物的过度活动减少程度显著更大且更持久，与 Li-7 和 Li 相比。这些结果表明，Li-6 可能比其母体化合物更有效地治疗躁狂症。
