Behavioral and pharmacological assessment of a potential new mouse model for mania

Scotti, Melissa-Ann L.; Lee, Grace; Stevenson, Sharon A.; Ostromecki, Alexandra M.; Wied, Tyler J.; Kula, Daniel J.; Gessay, Griffin M.; Gammie, Stephen C.

doi:10.1016/j.physbeh.2011.03.005

Cited by 25 publications

(28 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, several other mechanisms to account for the action of lithium have been proposed including inositol depletion, indirect activation of AKT, and inhibition of a β-arrestin/ AKT signaling complex (15,23,(48)(49)(50). Behavioral tests such as locomotion, tail-suspension test (TST), forced swim test (FST), and dark-light emergence test in mice are sensitive to lithium treatment (51,52). Previous work from our laboratory has shown that global βarr2 (βarr2 −/− ) or heterozygous GSK3β genetic deletion (GSK3β +/− ) or systemic pharmacological inhibition of GSK3β reduces DA-dependent hyperlocomotion, immobility time in the tail-suspension test as well as the latency to cross in the dark-light emergence test, thereby phenocopying the effects of lithium.…”

Section: Discussionmentioning

confidence: 99%

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

Urs¹,

Snyder²,

Jacobsen³

et al. 2012

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

View full text Add to dashboard Cite

Several studies in rodent models have shown that glycogen synthase kinase 3 β (GSK3β) plays an important role in the actions of antispychotics and mood stabilizers. Recently it was demonstrated that GSK3β through a β-arrestin2/protein kinase B (PKB or Akt)/protein phosphatase 2A (PP2A) signaling complex regulates dopamine (DA)-and lithium-sensitive behaviors and is required to mediate endophenotypes of mania and depression in rodents. We have previously shown that atypical antipsychotics antagonize DA D2 receptor (D2R)/β-arrestin2 interactions more efficaciously than G-protein-dependent signaling, whereas typical antipsychotics inhibit both pathways with similar efficacy. To elucidate the site of action of GSK3β in regulating DA-or lithium-sensitive behaviors, we generated conditional knockouts of GSK3β, where GSK3β was deleted in either DA D1-or D2-receptor-expressing neurons. We analyzed these mice for behaviors commonly used to test antipsychotic efficacy or behaviors that are sensitive to lithium treatment. Mice with deletion of GSK3β in D2 (D2GSK3β −/− ) but not D1 (D1GSK3β −/− ) neurons mimic antipsychotic action. However, haloperidol (HAL)-induced catalepsy was unchanged in either D2GSK3β −/− or D1GSK3β −/− mice compared with control mice. Interestingly, genetic stabilization of β-catenin, a downstream target of GSK3β, in D2 neurons did not affect any of the behaviors tested. Moreover, D2GSK3β −/− or D1GSK3β −/− mice showed similar responses to controls in the tail suspension test (TST) and dark-light emergence test, behaviors which were previously shown to be β-arrestin2-and GSK3β-dependent and sensitive to lithium treatment. Taken together these studies suggest that selective deletion of GSK3β but not stabilization of β-catenin in D2 neurons mimics antipsychotic action without affecting signaling pathways involved in catalepsy or certain mood-related behaviors.functional selectivity | schizophrenia | bipolar disorder | striatum | frontal cortex

show abstract

Section: Discussionmentioning

confidence: 99%

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

Urs¹,

Snyder²,

Jacobsen³

et al. 2012

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

View full text Add to dashboard Cite

show abstract

“…The FST is also used to assess mood disorder in rats and mice: an increase of immobility is considered to reflect a depressive mood, and is used as an index for depression or negative symptom of schizophrenia (Noda et al, 1995;. Several studies have reported a reduction of immobility in animal models of mania (Roybal et al, 2007;Mukherjee et al, 2010;Scotti et al, 2011), and the reduction of immobility was prevented by treatment with a mood stabilizer, Li (Roybal et al, 2007). Reduction of immobility is also considered an index for mania or an irritated mood state.…”

Section: Discussionmentioning

confidence: 99%

Behavioral and biochemical characterization of rats treated chronically with thioacetamide: proposal of an animal model for hepatic encephalopathy associated with cirrhosis

et al. 2012

View full text Add to dashboard Cite

-Hepatic encephalopathy (HE) is a syndrome observed in patients with liver dysfunction such as hepatitis and cirrhosis, and is characterized by cognitive impairment, personality changes, and a depressed level of consciousness. The detailed mechanism underlying the pathogenesis of HE remains unclear. In the present study, our aim was to establish an animal model for HE with cirrhosis. Therefore, we carried out behavioral and biochemical analysis of cirrhotic rats after treatment with thioacetamide (TAA) for 20 weeks. The rats subjected to chronic TAA treatment (TAA rats) showed reduction of cognitive scores in the novel object recognition test (NOR), and a decrease in immobility and an increase in swimming in the forced swim test (FST). In biochemical analyses, the TAA rats exhibited elevated blood levels of ammonia, and increased metabolic activities of serotonergic and noradrenergic neurons in the brain, while the levels of Glu and GABA were not affected. Post-oral treatment of lactulose, a clinically utilized drug for HE, effectively reduced the elevated blood ammonia levels, and restored the reduced cognitive scores and the decreased immobility, without any effects on neurotransmitter contents in the brain, compared with the control. These results indicated lactulose-restorable memory disturbance and irritated mood in the TAA rats. In other words, rats treated chronically with TAA are a potential model for cirrhosis-HE, and the combination of NOR and FST in TAA rats may be useful as a simple assay system for the screening and development of anti-HE agents.

show abstract

“…MSN mice display reduced anxiety and depression, increased sexual behavior, hyperactivity, and circadian abnormalities (Scotti et al, 2011, Saul et al, 2012, Saul et al, 2013). Lithium and olanzapine, an atypical antipsychotic, only reduced hyperactivity, with no changes observed for anxiety behavior in these mice (Scotti et al, 2011). In addition to face and predictive validity, MSN mice may also have high construct validity.…”

Section: Mouse Models Amenable To Systems Neuroscience and Functionalmentioning

confidence: 99%

Animal models of bipolar mania: The past, present and future

2016

View full text Add to dashboard Cite

Bipolar disorder (BD) is the sixth leading cause of disability in the world according to the World Health Organization and affects nearly 6 million (~2.5% of the population) adults in the United State alone each year. BD is primarily characterized by mood cycling of depressive (e.g., helplessness, reduced energy and activity, and anhedonia) and manic (e.g., increased energy and hyperactivity, reduced need for sleep, impulsivity, reduced anxiety and depression), episodes. The following review describes several animal models of bipolar mania with a focus on more recent findings using genetically modified mice, including several with the potential of investigating the mechanisms underlying ‘mood’ cycling (or behavioral switching in rodents). We discuss whether each of these models satisfy criteria of validity (i.e., face, predictive, and construct), while highlighting their strengths and limitations. Animal models are helping to address critical questions related to pathophysiology of bipolar mania, in an effort to more clearly define necessary targets of first-line medications, lithium and valproic acid, and to discover novel mechanisms with the hope of developing more effective therapeutics. Future studies will leverage new technologies and strategies for integrating animal and human data to reveal important insights into the etiology, pathophysiology, and treatment of BD.

show abstract

Behavioral and pharmacological assessment of a potential new mouse model for mania

Cited by 25 publications

References 57 publications

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

Behavioral and biochemical characterization of rats treated chronically with thioacetamide: proposal of an animal model for hepatic encephalopathy associated with cirrhosis

Animal models of bipolar mania: The past, present and future

Contact Info

Product

Resources

About