The behavioral actions of lithium in rodent models: leads to develop novel therapeutics

Abstract

For nearly as long as lithium has been in clinical use for the treatment of bipolar disorder, depression, and other conditions, investigators have attempted to characterize its effects on behaviors in rodents. Lithium consistently decreases exploratory activity, rearing, aggression, and amphetamine-induced hyperlocomotion; and it increases the sensitivity to pilocarpine-induced seizures, decreases immobility time in the forced swim test, and attenuates reserpine-induced hypolocomotion. Lithium also predictably induces conditioned taste aversion and alterations in circadian rhythms. The modulation of stereotypy, sensitization, and reward behavior are less consistent actions of the drug. These behavioral models may be relevant to human symptoms and to clinical endophenotypes. It is likely that the actions of lithium in a subset of these animal models are related to the therapeutic efficacy, as well the side effects, of the drug. We conclude with a brief discussion of various molecular mechanisms by which these lithium-sensitive behaviors may be mediated, and comment on the ways in which rat and mouse models can be used more effectively in the future to address persistent questions about the therapeutically relevant molecular actions of lithium.

Figure 1. Lithium: loci of preclinical research

The mechanism by which lithium exerts its therapeutic effects is investigated from a number of perspectives. The cation directly inhibits a select group of enzymes, included in which are inositol monophosphatase (IMPase), inositol polyphosphate 1-phosphatase (IPPase), phosphoglucomutase (PGMase), biphosphate nucleotidase (BPNase), fructose 1,6-biphosphatase (FBPase), and glycogen synthase kinase-3 (GSK-3). The study of these direct targets can provide insight to the ability of lithium to modulate intracellular signaling cascades, the downstream consequences of which are its effects on physiology and behavior. Ideally, the study of behavior will in turn provide insight on which of the immediate targets of lithium is relevant to its therapeutic effects. Abbreviations: cAMP: cyclic adenosine monophosphate; ERK-MAPK: extracellular signal-regulated kinase-mitogen-activated protein kinase; FST: forced swim test; PI3K: phosphatidylinositol 3-kinase; PKC: protein kinase C.