Neurobehavioral effects of lithium in the rat: Investigation of the effect/concentration relationships and the contribution of the poisoning pattern

Anne-Sophie Hanak; Lucie Chevillard; Rodolphe Lebeau; Patricia Risède; Jean-Louis Laplanche; Nadia Benturquia; Bruno Mégarbane

doi:10.1016/j.pnpbp.2017.03.005

Neurobehavioral effects of lithium in the rat: Investigation of the effect/concentration relationships and the contribution of the poisoning pattern

Prog Neuropsychopharmacol Biol Psychiatry. 2017 Jun 2:76:124-133. doi: 10.1016/j.pnpbp.2017.03.005. Epub 2017 Mar 20.

Authors

Anne-Sophie Hanak¹, Lucie Chevillard¹, Rodolphe Lebeau¹, Patricia Risède¹, Jean-Louis Laplanche¹, Nadia Benturquia¹, Bruno Mégarbane²

Affiliations

¹ Inserm, UMR-S1144, Paris, France; Paris-Descartes University, Paris, France; Paris-Diderot University, Paris, France.
² 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. Electronic address: bruno-megarbane@wanadoo.fr.

PMID: 28336491
DOI: 10.1016/j.pnpbp.2017.03.005

Abstract

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_max 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.

Keywords: Behavior; Effect/concentration relationships; Lithium; Locomotor activity; Poisoning.

MeSH terms

Anhedonia / drug effects*
Animals
Antidepressive Agents / poisoning*
Behavior, Animal / drug effects*
Disease Models, Animal
Lithium Compounds / poisoning*
Male
Motor Activity / drug effects*
Rats
Rats, Sprague-Dawley
Spatial Memory / drug effects*

Substances

Antidepressive Agents
Lithium Compounds