Antipsychotic Drugs: Comparison in Animal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection

Lieberman, Jeffrey A.; Bymaster, Frank P.; Meltzer, Herbert Y.; Deutch, Ariel Y.; Duncan, Gary E.; Marx, Christine E.; Aprille, June R.; Dwyer, Donard S.; Li, Xin Min; Mahadik, Sahebarao P.; Duman, Ronald S.; Porter, Joseph H.; Modica-Napolitano, Josephine S.; Newton, Samuel S.; Csernansky, John G.

doi:10.1124/pr.107.00107

Cited by 209 publications

(182 citation statements)

References 611 publications

(765 reference statements)

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“…Hyperdopaminergia, a well-accepted model of psychosis, is known to induce hyperlocomotion and disrupt prepulse inhibition (PPI), whereas inhibition of the DA system by haloperidol induces catalepsy in mice (19). Inhibition of hyperlocomotion, reversal of disrupted PPI, and cataleptic potential are commonly used behavioral tests in rodents to assess efficacy of antipsychotics (19,20). We therefore sought to delineate the effect of neuronalspecific deletion of GSK3β on hyperlocomotion, PPI, and haloperidol (HAL)-induced catalepsy.…”

Section: Resultsmentioning

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.

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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

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Section: Resultsmentioning

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.

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“…One of the key neural sites of antipsychotic action is the nucleus accumbens shell (Deutch et al, 1992;Robertson et al, 1994;Semba et al, 1999) as both typical and atypical antipsychotic drug induce c-Fos expression in this brain region. These effects have been related to the therapeutic properties of antipsychotic drugs (Lieberman et al, 2008;Robertson et al, 1994). More recently, the prefrontal cortex has been identified as another brain subregion area that may be involved in antipsychotic efficacy (Wadenberg et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation

Montalvo-Ortiz

Keegan

Gallardo

et al. 2013

Neuropsychopharmacol

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Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psychopathological conditions, including psychosis and the behavioral disturbances associated with dementia. However, clinical experience suggests that these drugs may be less efficacious in the elderly individuals than in the young. Recent studies suggest that aging may be associated with epigenetic changes and that valproic acid (VPA), a histone deacetylase inhibitor, may reverse such changes. However, it is not yet known whether HDAC inhibitors can modulate age-related epigenetic changes that may impact antipsychotic drug action. In this study, we analyzed conditioned avoidance response (CAR) and c-Fos expression patterns to elucidate the effect of HDAC inhibitors VPA and entinostat (MS-275) on behavioral and molecular markers of the effects of haloperidol (HAL) in aged mice. Our results showed that HAL administration failed to suppress the avoidance response during the CAR test, suggesting an age-related decrease in drug efficacy. In addition, HAL-induced c-Fos expression in the nucleus accumbens shell and prefrontal cortex was significantly lower in aged mice as compared with young mice. Pretreatment with VPA and MS-275 significantly improved HAL effects on the CAR test in aged mice. Also, VPA and MS-275 pretreatment restored HAL-induced increases in c-Fos expression in the nucleus accumbens shell and prefrontal cortex of aged mice to levels comparable with those observed in young mice. Lastly, but most importantly, increases in c-Fos expression and HAL efficacy in the CAR test of the HAL þ VPA and HAL þ MS-275 groups were correlated with elevated histone acetylation at the c-fos promoter region in aged mice. These findings suggest that pretreatment with VPA or MS-275 increases the behavioral and molecular effects of HAL in aged mice and that these effects occur via modulation of age-related histone hypoacetylation in the nucleus accumbens shell and prefrontal cortex.

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“…A new generation of antipsychotic drugs, the atypical antipsychotics (for example quetiapine, olanzapine, risperidone and clozapine), with a lower affinity and occupancy for the dopaminergic receptors, but an additional occupancy for the serotoninergic 5-HT 2A and other receptors [8] have become available. Antipsychotics are effective in reducing the severity of positive psychotic symptoms but have limited impact on negative symptoms, cognitive impairment and produce a range of side effects including extra-pyramidal symptoms, prolactin elevation, sedation and cardio-metabolic effects [7]. Compared to typical antipsychotics, atypical antipsychotics induce less extra-pyramidal adverse effects and more metabolic adverse *Address correspondence to this author at the Psychiatric Outpatient Department, Medical Image Analysis Centre, Petersgraben 4, CH-4031 Basel, Switzerland; Tel: 0041613286126; Fax: 0041612654588; E-mail: sborgwardt@uhbs.ch effects [7] but the underlying neurobiological mechanisms are still unclear.…”

Section: Introductionmentioning

confidence: 99%

“…A large body of neuroimaging studies have reported that as the illness proceeds, patients rapidly lose cerebral gray matter (GM), particularly in the frontal, temporal and limbic lobes [3,4]. The treatment of schizophrenia involves the use of antipsychotic drugs (typical antipsychotics, such as haloperidol), which act as antagonists at central dopamine D 2 receptors [5,6], although some of them have additional effects on other receptors [7]. A new generation of antipsychotic drugs, the atypical antipsychotics (for example quetiapine, olanzapine, risperidone and clozapine), with a lower affinity and occupancy for the dopaminergic receptors, but an additional occupancy for the serotoninergic 5-HT 2A and other receptors [8] have become available.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Antipsychotics on the Brain: What Have We Learnt from Structural Imaging of Schizophrenia? – A Systematic Review

Smieskova

Fusar‐Poli²,

Allen³

et al. 2009

CPD

186

131

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Abstract:Despite a large number of neuroimaging studies in schizophrenia reporting subtle brain abnormalities, we do not know to what extent such abnormalities reflect the effects of antipsychotic treatment on brain structure. We therefore systematically reviewed cross-sectional and follow-up structural brain imaging studies of patients with schizophrenia treated with antipsychotics. 30 magnetic resonance imaging (MRI) studies were identified, 24 of them being longitudinal and six cross-sectional structural imaging studies. In patients with schizophrenia treated with antipsychotics, reduced gray matter volume was described, particularly in the frontal and temporal lobes. Structural neuroimaging studies indicate that treatment with typical as well as atypical antipsychotics may affect regional gray matter (GM) volume. In particular, typical antipsychotics led to increased gray matter volume of the basal ganglia, while atypical antipsychotics reversed this effect after switching. Atypical antipsychotics, however, seem to have no effect on basal ganglia structure.

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Antipsychotic Drugs: Comparison in Animal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection

Cited by 209 publications

References 611 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

HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation

The Effects of Antipsychotics on the Brain: What Have We Learnt from Structural Imaging of Schizophrenia? – A Systematic Review

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