GBR 12909 administration as a mouse model of bipolar disorder mania: mimicking quantitative assessment of manic behavior

Young, Jared W.; Goey, Andrew K.L.; Minassian, Arpi; Perry, William; Paulus, Martin P.; Geyer, Mark A.

doi:10.1007/s00213-009-1744-8

Cited by 66 publications

(80 citation statements)

References 67 publications

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“…The utility of the BPM used in these studies goes beyond measures of the amount of activity by assessing a profile of exploratory behavior. This multivariate approach has proven useful in differentiating between stimulants in rats (Geyer et al, 1986) and mice (Young et al, 2010a), and also in characterizing human psychiatric and healthy populations (Perry et al, 2009;Young et al, 2007b). In these studies, modafinil not only increased activity, but also increased specific exploration (increased rearing/holepoking) and increased the linearity of the movement patterns of the animals (reduced spatial d).…”

Section: Discussionmentioning

confidence: 97%

“…We previously described the behavioral pattern monitor (BPM) as a useful method to differentiate the mechanisms of action of diverse stimulants, such as NMDA-mediated PCP, DAT/NETmediated amphetamine or GBR12909, or muscarinic acetylcholine receptor-mediated scopolamine (Geyer et al, 1986;Perry et al, 2009;Young et al, 2010aYoung et al, , 2007b. The BPM provides multiple measures, which can be reduced to three principal factorsFdiversive exploration or the amount of activity, inspective exploration of specific stimuli, and spatiotemporal patterns of locomotion (Paulus and Geyer, 1993).…”

Section: Introductionmentioning

confidence: 99%

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Dopamine Receptor Mediation of the Exploratory/Hyperactivity Effects of Modafinil

Young

Kooistra

Geyer

2011

Neuropsychopharmacol

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Modafinil (2-((diphenylmethyl)sulfinyl)acetamide) is described as an atypical stimulant and is a putative cognition enhancer for schizophrenia, but the precise mechanisms of action remain unclear. Receptor knockout (KO) mice offer an opportunity to identify receptors that contribute to a drug-induced effect. Here we examined the effects of modafinil on exploration in C57BL/6J mice, in dopamine drd1, drd2, drd3, and drd4 wild-type (WT), heterozygous (HT), and KO mice, and in 129/SJ mice pretreated with the drd1 antagonist SCH23390 using a cross-species test paradigm based on the behavioral pattern monitor. Modafinil increased activity, specific exploration (rearing), and the smoothness of locomotor paths (reduced spatial d) in C57BL/6J and 129/SJ mice (increased holepoking was also observed in these mice). These behavioral profiles are similar to that produced by the dopamine transporter inhibitor GBR12909. Modafinil was ineffective at increasing activity in male drd1 KOs, rearing in female drd1 KOs, or reducing spatial d in all drd1 KOs, but produced similar effects in drd1 WT and HT mice as in C57BL/6J mice. Neither dopamine drd2 nor drd3 mutants attenuated modafinil-induced effects. Drd4 mutants exhibited a genotype dose-dependent attenuation of modafinil-induced increases in specific exploration. Furthermore, the drd1 KO effects were largely supported by the SCH23390 study. Thus, the dopamine drd1 receptor appears to exert a primary role in modafinil-induced effects on spontaneous exploration, whereas the dopamine drd4 receptor appears to be important for specific exploration. The modafinil-induced alterations in exploratory behavior may reflect increased synaptic dopamine and secondary actions mediated by dopamine drd1 and drd4 receptors.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Dopamine Receptor Mediation of the Exploratory/Hyperactivity Effects of Modafinil

Young

Kooistra

Geyer

2011

Neuropsychopharmacol

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“…GBR12909 dihydrochloride was purchased from Sigma Aldrich (St Louis, MO, USA) and dissolved in saline after heating (45 1C, 60 min;van Enkhuizen et al, 2013a;Young et al, 2010). GBR12909 was injected intraperitoneally with a volume of 10 ml/kg, immediately before testing.…”

Section: Drugsmentioning

confidence: 99%

“…After stabilization of responding, C57BL/6J mice (n ¼ 89) naïve to the IGT received saline (n ¼ 29), GBR12909 at 9 (n ¼ 30) or 16 mg/kg (n ¼ 30; van Enkhuizen et al, 2013b;Young et al, 2010) and were challenged in the IGT.…”

Section: Effects Of Acute Reductions Of Dat Functioning On Igt Performentioning

confidence: 99%

Reduced Dopamine Transporter Functioning Induces High-Reward Risk-Preference Consistent with Bipolar Disorder

Enkhuizen

Henry

Minassian

et al. 2014

Neuropsychopharmacol

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Individuals with bipolar disorder (BD) exhibit deleterious decision making, negatively impacting their lives. Such aberrant decision making can be quantified using the Iowa Gambling Task (IGT), which requires choosing between advantageous and disadvantageous options based on different reward/punishment schedules. The mechanisms underlying this behavioral deficit are unknown, but may include the reduced dopamine transporter (DAT) functioning reported in BD patients. Using both human and mouse IGTs, we tested whether reduced DAT functioning would recreate patterns of deficient decision making of BD patients. We assessed the IGT performance of 16 BD subjects (7 female) and 17 healthy control (HC) subjects (12 female). We recorded standard IGT performance measures and novel post-reward and post-punishment decision-making strategies. We characterized a novel single-session mouse IGT using C57BL/6J mice (n ¼ 44). The BD and HC IGT performances were compared with the effects of chronic (genetic knockdown (KD; n ¼ 31) and wild-type (n ¼ 28) mice) and acute (C57BL/6J mice (n ¼ 89) treated with the DAT inhibitor GBR12909) reductions of DAT functioning in mice performing this novel IGT. BD patients exhibited impaired decision making compared with HC subjects. Both the good-performing DAT KD and GBR12909-treated mice exhibited poor decision making in the mouse IGT. The deficit of each population was driven by highreward sensitivity. The single-session mouse IGT measures dynamic risk-based decision making similar to humans. Chronic and acute reductions of DAT functioning in mice impaired decision-making consistent with poor IGT performance of BD patients. Hyperdopaminergia caused by reduced DAT may impact poor decision making in BD patients, which should be confirmed in future studies.

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“…exploratory locomotion is a known behavioral effect of GSK3β inhibition that is used to model "antimanic" effects (21,22). Furthermore, lithium treatments and inhibition of GSK3β have been shown to exert an effect similar to antidepressants by reducing immobility in the tail suspension test (TST) (8,(23)(24)(25).…”

Section: Significancementioning

confidence: 99%

FXR1P is a GSK3β substrate regulating mood and emotion processing

Del’Guidice

Latapy

Rampino

et al. 2015

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

112

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Inhibition of glycogen synthase kinase 3β (GSK3β) is a shared action believed to be involved in the regulation of behavior by psychoactive drugs such as antipsychotics and mood stabilizers. However, little is known about the identity of the substrates through which GSK3β affects behavior. We identified fragile X mental retardation-related protein 1 (FXR1P), a RNA binding protein associated to genetic risk for schizophrenia, as a substrate for GSK3β. Phosphorylation of FXR1P by GSK3β is facilitated by prior phosphorylation by ERK2 and leads to its down-regulation. In contrast, behaviorally effective chronic mood stabilizer treatments in mice inhibit GSK3β and increase FXR1P levels. In line with this, overexpression of FXR1P in the mouse prefrontal cortex also leads to comparable mood-related responses. Furthermore, functional genetic polymorphisms affecting either FXR1P or GSK3β gene expression interact to regulate emotional brain responsiveness and stability in humans. These observations uncovered a GSK3β/FXR1P signaling pathway that contributes to regulating mood and emotion processing. Regulation of FXR1P by GSK3β also provides a mechanistic framework that may explain how inhibition of GSK3β can contribute to the regulation of mood by psychoactive drugs in mental illnesses such as bipolar disorder. Moreover, this pathway could potentially be implicated in other biological functions, such as inflammation and cell proliferation, in which FXR1P and GSK3 are known to play a role.

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GBR 12909 administration as a mouse model of bipolar disorder mania: mimicking quantitative assessment of manic behavior

Cited by 66 publications

References 67 publications

Dopamine Receptor Mediation of the Exploratory/Hyperactivity Effects of Modafinil

Dopamine Receptor Mediation of the Exploratory/Hyperactivity Effects of Modafinil

Reduced Dopamine Transporter Functioning Induces High-Reward Risk-Preference Consistent with Bipolar Disorder

FXR1P is a GSK3β substrate regulating mood and emotion processing

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