Lithium attenuates Drug-induced Hyperactivity in Rats

Cox, Maria Christina; Harrison-Read, Phil; Steinberg, Hannah; Maciej, TOMKIEWICZ,

doi:10.1038/232336a0

Cited by 91 publications

(31 citation statements)

References 16 publications

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“…The effect of lithium to attenuate stimulant-induced hyperlocomotion in both mice and rats is very consistent in the literature (Cox et al, 1971;Davies et al, 1974). However, mixed results have been found regarding the effect of lithium on stimulant-induced stereotypy.…”

Section: Discussionsupporting

confidence: 83%

“…The effect of lithium to attenuate stimulant-induced hyperlocomotion in rodents has been widely replicated and is considered a model of the antimanic properties of the drug (Cox et al, 1971;Davies et al, 1974). A single injection of 100 mg/kg lithium chloride 15 min before 2 mg/kg damphetamine attenuated hyperlocomotion in C57BL/6J mice over a period of 90 min (Figure 4a).…”

Section: D-amphetamine Hyperlocomotionmentioning

confidence: 98%

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β-Catenin Overexpression in the Mouse Brain Phenocopies Lithium-Sensitive Behaviors

Gould

Einat

O’Donnell

et al. 2007

Neuropsychopharmacol

128

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Lithium inhibits glycogen synthase kinase-3 (GSK-3) at therapeutic concentrations; however, it is unclear if this inhibition and its downstream effects on specific signaling pathways are relevant to the treatment of bipolar disorder and depression. One of the targets of GSK-3 is the transcription factor b-catenin. Normally active GSK-3 phosphorylates b-catenin, leading to its degradation. Inhibition of GSK-3 therefore increases b-catenin. We have utilized transgenic mice to investigate the behavioral consequences of CNS b-catenin overexpression. Transgenic mice overexpressing b-catenin demonstrated behavioral changes similar to those observed following the administration of lithium, including decreased immobility time in the forced swim test (FST). Further, we show that although acute administration of lithium and overexpression of the b-catenin transgene inhibits d-amphetamine-induced hyperlocomotion, neither lithium nor the b-catenin transgene prevents d-amphetamine-induced sensitization, as measured by locomotor activity. Both lithiumtreated and b-catenin mice had an elevated response to d-amphetamine following multiple administrations of the stimulant, though the difference in absolute locomotion was maintained throughout the sensitization time-course. Neither acute lithium nor b-catenin overexpression had an effect on d-amphetamine-induced stereotyped behavior. The results of this study, in which b-catenin transgenic mice exhibited behaviors identical to those observed in lithium-treated mice, are consistent with the hypothesis that the behavioral effects of lithium in these models are mediated through its direct inhibition of GSK-3 and the consequent increase in b-catenin. By associating the behavioral effects of lithium with b-catenin levels, these data suggest that increasing b-catenin might be a novel therapeutic strategy for mood disorders.

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Section: Discussionsupporting

confidence: 83%

Section: D-amphetamine Hyperlocomotionmentioning

confidence: 98%

β-Catenin Overexpression in the Mouse Brain Phenocopies Lithium-Sensitive Behaviors

Gould

Einat

O’Donnell

et al. 2007

Neuropsychopharmacol

128

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“…Certain aspects of this endophenotype can be explored in animal models; for example, the mouse model of amphetamine-induced hyperlocomotion, although not an endophenotype itself, may provide a means of investigating the altered neurobiological response to amphetamine reported in clinical studies. In 1971, Cox et al (1971) reported that lithium attenuated stimulant-induced hyperlocomotion in rats. This effect was later reported in mice (Berggren et al, 1978;Borison et al, 1978).…”

Section: Introductionmentioning

confidence: 99%

Strain Differences in Lithium Attenuation of d-Amphetamine-Induced Hyperlocomotion: A Mouse Model for the Genetics of Clinical Response to Lithium

Gould

O’Donnell

Picchini

et al. 2006

Neuropsychopharmacol

109

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Lithium attenuation of stimulant-induced hyperlocomotion is a rodent model that may be useful both to understand the mechanism of the therapeutic action of lithium and to develop novel lithium-mimetic compounds. To lay the foundation for future investigations into the neurobiology and genetics of lithium as a therapeutic agent, we studied the effect of lithium on d-amphetamine-induced hyperlocomotion in 12 (3 outbred) mouse strains. In our initial screening, mice received either (1) no drugs, (2) LiCl only, (3) damphetamine only, or (4) d-amphetamine and LiCl. Whereas there was no significant effect of LiCl alone on locomotion in any strain, there was a large degree of strain variation in the effects of LiCl combined with d-amphetamine. LiCl attenuated d-amphetamine-induced hyperlocomotion in C57BL/6J, C57BL/6Tac, Black Swiss, and CBA/J mice, whereas CD-1, FVB/NJ, SWR/J, and NIH Swiss mice, which were responsive to d-amphetamine, showed no significant effect of LiCl. d-Amphetamine-induced hyperlocomotion in the C3H/HeJ strain was increased by pretreatment with lithium. A subset of strains were treated for 4 weeks with lithium carbonate before the damphetamine challenge, and in each of these strains, lithium produced effects identical to those seen following acute administration. Strain responsiveness to lithium was not dependent upon the dose of either d-amphetamine or LiCl. Further, the results are not explained by brain lithium levels, which suggests that these behavioral responses to lithium are under the control of inherent genetic or other biological mechanisms specific to the effects of lithium on brain function.

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“…However, the signaling mechanisms mediating the action of DA on hyperactivity are still not fully understood. For instance, acute administration of lithium salts is known to antagonize the hyperactivity induced by various dopaminergic agonists (8)(9)(10)(11). Nevertheless, the mechanism by which lithium interferes with DA-associated behavior remains uncharacterized.…”

mentioning

confidence: 99%

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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Lithium attenuates Drug-induced Hyperactivity in Rats

Cited by 91 publications

References 16 publications

β-Catenin Overexpression in the Mouse Brain Phenocopies Lithium-Sensitive Behaviors

β-Catenin Overexpression in the Mouse Brain Phenocopies Lithium-Sensitive Behaviors

Strain Differences in Lithium Attenuation of d-Amphetamine-Induced Hyperlocomotion: A Mouse Model for the Genetics of Clinical Response to Lithium

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

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