The pharmacokinetic profile of lithium in rat and mouse; An important factor in psychopharmacological investigation of the drug

Wood, A. J.; Goodwin, Guy M.; Souza, Raquel De; Green, A R

doi:10.1016/0028-3908(86)90149-8

Cited by 66 publications

(46 citation statements)

References 7 publications

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“…In DAT-KO mice the DA-dependent hyperactivity and stereotypy that develop after the exposure of the mice to a novel environment (5) can be significantly attenuated by LiCl. Administration of LiCl at doses known not to induce toxicity in mice (16)(17)(18) resulted in a rapid inhibition of horizontal activity that was maintained for at least 1 h after injection (Fig. 1A).…”

Section: Resultsmentioning

confidence: 97%

Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade

Beaulieu

Sotnikova

Yao

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

725

903

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Dopamine (DA) is a neurotransmitter involved in the control of locomotion, emotion, cognition, and reward. Administration of lithium salts is known to inhibit DA-associated behaviors in experimental animal models through unknown mechanisms. Here, we used a pharmacogenetic approach to show that DA can exert its behavioral effects by acting on a lithium-sensitive signaling cascade involving Akt͞PKB and glycogen synthase kinase 3 (GSK-3). In the mouse striatum, increased DA neurotransmission arising either from administration of amphetamine or from the lack of the DA transporter results in inactivation of Akt and concomitant activation of GSK-3␣ and GSK-3␤. These biochemical changes are not affected by activation of the cAMP pathway but are effectively reversed either by inhibition of DA synthesis, D2 receptor blockade, or administration of lithium salts. Furthermore, pharmacological or genetic inhibition of GSK-3 significantly reduces DA-dependent locomotor behaviors. These data support the involvement of GSK-3 as an important mediator of DA and lithium action in vivo and suggest that modulation of the Akt͞GSK-3 pathway might be relevant to DA-related disorders, such as attention deficit hyperactivity disorder and schizophrenia.

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Section: Resultsmentioning

confidence: 97%

Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade

Beaulieu

Sotnikova

Yao

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

725

903

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“…1 B). Lithium was undetectable in the serum of mice that were switched to control chow (lithium is cleared in C57/B6 mice with a half-life of 2.6 hr) (Wood et al, 1986). Lithium-treated animals showed decreased time immobile (Fig.…”

Section: Forced Swim Testmentioning

confidence: 95%

Glycogen Synthase Kinase-3β Haploinsufficiency Mimics the Behavioral and Molecular Effects of Lithium

O’Brien

Harper²,

Jové³

et al. 2004

J. Neurosci.

402

376

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Lithium is widely used to treat bipolar disorder, but its mechanism of action in this disorder is unknown. Several molecular targets of lithium have been identified, but these putative targets have not been shown to be responsible for the behavioral effects of lithium in vivo. A robust model for the effects of chronic lithium on behavior in mice would greatly facilitate the characterization of lithium action. We describe behaviors in mice that are robustly affected by chronic lithium. Remarkably, these lithium-sensitive behaviors are also observed in mice lacking one copy of the gene encoding glycogen synthase kinase-3␤ (Gsk-3␤), a well established direct target of lithium. In addition, chronic lithium induces molecular changes consistent with inhibition of GSK-3 within regions of the brain that are paralleled in Gsk-3␤ ϩ/Ϫ heterozygous mice. We also show that lithium therapy activates Wnt signaling in vivo, as measured by increased Wntdependent gene expression in the amygdala, hippocampus, and hypothalamus. These observations support a central role for GSK-3␤ in mediating behavioral responses to lithium.

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“…Because the pharmacokinetics of lithium in humans is considerably different from what is found in rodents, a considerably higher lithium-by-weight dose may be applied in behavioral models. However, lithium metabolism in rats and mice is not identical, and particular caution must be taken when attempting to apply to rats a dosing paradigm used with mice, as the former metabolize lithium more slowly, and thus often require a lower dose than would mice (Wood et al, 1986). High levels of lithium can cause non-specific toxic effects, and can influence baseline behavior (thus confounding test results), making appropriate dosing all the more critical (Smith, 1978).…”

Section: Box 1: Lithium Dosage In Behavioral Studiesmentioning

confidence: 99%

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

O’Donnell

Gould

2007

Neuroscience & Biobehavioral Reviews

121

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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.

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The pharmacokinetic profile of lithium in rat and mouse; An important factor in psychopharmacological investigation of the drug

Cited by 66 publications

References 7 publications

Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade

Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade

Glycogen Synthase Kinase-3β Haploinsufficiency Mimics the Behavioral and Molecular Effects of Lithium

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

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