Hanak Anne-Sophie, Chevillard Lucie, Lebeau Rodolphe, Risède Patricia, Laplanche Jean-Louis, Benturquia Nadia, Mégarbane Bruno
Inserm, UMR-S1144, Paris, France; Paris-Descartes University, Paris, France; Paris-Diderot University, Paris, France.
Inserm, UMR-S1144, Paris, France; Paris-Descartes University, Paris, France; Paris-Diderot University, Paris, France; Assistance Publique - Hôpitaux de Paris, Lariboisière Hospital, Department of Medical and Toxicological Critical Care, Paris, France.
Prog Neuropsychopharmacol Biol Psychiatry. 2017 Jun 2;76:124-133. doi: 10.1016/j.pnpbp.2017.03.005. Epub 2017 Mar 20.
Severity of lithium poisoning depends on the ingested dose, previous treatment duration and renal function. No animal study has investigated neurobehavioral differences in relation to the lithium poisoning pattern observed in humans, while differences in lithium pharmacokinetics have been reported in lithium-pretreated rats mimicking chronic poisonings with enhanced brain accumulation in rats with renal failure. Our objectives were: 1)-to investigate lithium-related effects in overdose on locomotor activity, anxiety-like behavior, spatial recognition memory and anhedonia in the rat; 2)-to model the relationships between lithium-induced effects on locomotion and plasma, erythrocyte, cerebrospinal fluid and brain concentrations previously obtained according to the poisoning pattern. Open-field, elevated plus-maze, Y-maze and sucrose consumption tests were used. In acutely lithium-poisoned rats, we observed horizontal (p<0.001) and vertical hypolocomotion (p<0.0001), increased anxiety-like behavior (p<0.05) and impaired memory (p<0.01) but no altered hedonic status. Horizontal (p<0.01) and vertical (p<0.001) hypolocomotion peaked more markedly 24h after lithium injection and was more prolonged in acute-on-chronically vs. acutely lithium-poisoned rats. Hypolocomotion in chronically lithium-poisoned rats with impaired renal function did not differ from acutely poisoned rats 24h after the last injection. Interestingly, hypolocomotion/concentration relationships best fitted a sigmoidal E model in acute poisoning and a linear regression model linked to brain lithium in acute-on-chronic poisoning. In conclusion, lithium overdose alters rat behavior and consistently induces hypolocomotion which is more marked and prolonged in repeatedly lithium-treated rats. Our data suggest that differences between poisoning patterns regarding lithium-induced hypolocomotion are better explained by the duration of lithium exposure than by its brain accumulation.
锂中毒的严重程度取决于摄入剂量、先前的治疗时长以及肾功能。尚无动物研究调查过与人类所观察到的锂中毒模式相关的神经行为差异，不过在模拟慢性中毒的锂预处理大鼠中，已报道了锂药代动力学的差异，肾衰竭大鼠的脑内蓄积增强。我们的目标是：1）研究大鼠过量摄入锂对运动活动、焦虑样行为、空间识别记忆和快感缺失的影响；2）根据中毒模式，模拟锂对运动的影响与先前获得的血浆、红细胞、脑脊液和脑内浓度之间的关系。使用旷场试验、高架十字迷宫试验、Y迷宫试验和蔗糖消耗试验。在急性锂中毒大鼠中，我们观察到水平运动减少（p<0.001）和垂直运动减少（p<0.0001）、焦虑样行为增加（p<0.05）以及记忆受损（p<0.01），但快感状态未改变。水平运动减少（p<0.01）和垂直运动减少（p<0.001）在锂注射后24小时更为明显，并且在急性加慢性锂中毒大鼠中比急性锂中毒大鼠持续时间更长。肾功能受损的慢性锂中毒大鼠在最后一次注射后24小时的运动减少情况与急性中毒大鼠无差异。有趣的是，急性中毒时运动减少/浓度关系最符合S形E模型，而急性加慢性中毒时则符合与脑内锂相关的线性回归模型。总之，锂过量会改变大鼠行为，并持续诱导运动减少，在反复接受锂治疗的大鼠中更为明显且持续时间更长。我们的数据表明，锂诱导的运动减少在中毒模式上的差异，用锂暴露时长比用脑内蓄积来解释更好。
