Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

Deng, Chao; Pan, Bo; Hu, Changhua; Han, Mei; Huang, Xu‐Feng

doi:10.1016/j.psychres.2014.12.014

Cited by 12 publications

(8 citation statements)

References 80 publications

(109 reference statements)

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“…A link between NRG1 and D2Rs in controlling psychotic-like behavior in rodents has recently been shown [ 110 ]. Distinct temporal and spatial downregulation may be induced by chronic aripiprazole, olanzapine, or haloperidol treatment on different NRG1 isoforms, thus confirming the unique features of functional selectivity among antipsychotic drugs [ 111 ].…”

Section: Pharmacodynamic Properties Of Aripiprazolementioning

confidence: 93%

Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies Beyond Dopamine Receptor Antagonism

Bartolomeis¹,

Tomasetti²,

Iasevoli³

2015

CNS Drugs

133

106

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Dopamine partial agonism and functional selectivity have been innovative strategies in the pharmacological treatment of schizophrenia and mood disorders and have shifted the concept of dopamine modulation beyond the established approach of dopamine D2 receptor (D2R) antagonism. Despite the fact that aripiprazole was introduced in therapy more than 12 years ago, many questions are still unresolved regarding the complexity of the effects of this agent on signal transduction and intracellular pathways, in part linked to its pleiotropic receptor profile. The complexity of the mechanism of action has progressively shifted the conceptualization of this agent from partial agonism to functional selectivity. From the induction of early genes to modulation of scaffolding proteins and activation of transcription factors, aripiprazole has been shown to affect multiple cellular pathways and several cortical and subcortical neurotransmitter circuitries. Growing evidence shows that, beyond the consequences of D2R occupancy, aripiprazole has a unique neurobiology among available antipsychotics. The effect of chronic administration of aripiprazole on D2R affinity state and number has been especially highlighted, with relevant translational implications for long-term treatment of psychosis. The hypothesized effects of aripiprazole on cell-protective mechanisms and neurite growth, as well as the differential effects on intracellular pathways [i.e. extracellular signal-regulated kinase (ERK)] compared with full D2R antagonists, suggest further exploration of these targets by novel and future biased ligand compounds. This review aims to recapitulate the main neurobiological effects of aripiprazole and discuss the potential implications for upcoming improvements in schizophrenia therapy based on dopamine modulation beyond D2R antagonism.

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Section: Pharmacodynamic Properties Of Aripiprazolementioning

confidence: 93%

Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies Beyond Dopamine Receptor Antagonism

Bartolomeis¹,

Tomasetti²,

Iasevoli³

2015

CNS Drugs

133

106

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“…The dosages were translated from recommended clinical dosages based on body surface area according to the FDA guidelines [ 30 , 31 ]. This drug administration method has been well established in our laboratory [ 32 , 33 ]. Specifically, a 0.75 mg/kg aripiprazole, 0.8 mg/kg bifeprunox and 0.1 mg/kg haloperidol dosage in rats is equivalent to ~7.5, ~8, and ~1 mg in humans (60 kg body weight), respectively, all of which are within the used/recommended clinical dosages [ 34 , 35 , 36 ].…”

Section: Methodsmentioning

confidence: 99%

“…The Western blot experiments were performed following standard procedures repeated in our previous studies [ 8 , 33 ]. Briefly, frozen tissue was homogenised with 9.8 mL NP-40 cell lysis buffer (Invitrogen, Camarillo, CA, USA) containing 100 μL Protease Inhibitor Cocktail (Sigma-Aldrich, St. Louis, MO, USA), 100 μL β-Glycerophosphate (Invitrogen) and 33.3 μL phenylmethylsulfonylfluoride (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

Aripiprazole and Haloperidol Activate GSK3β-Dependent Signalling Pathway Differentially in Various Brain Regions of Rats

Pan

Huang

Deng

2016

IJMS

Self Cite

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Aripiprazole, a dopamine D2 receptor (D2R) partial agonist, possesses a unique clinical profile. Glycogen synthase kinase 3β (GSK3β)-dependent signalling pathways have been implicated in the pathophysiology of schizophrenia and antipsychotic drug actions. The present study examined whether aripiprazole differentially affects the GSK3β-dependent signalling pathways in the prefrontal cortex (PFC), nucleus accumbens (NAc), and caudate putamen (CPu), in comparison with haloperidol (a D2R antagonist) and bifeprunox (a D2R partial agonist). Rats were orally administrated aripiprazole (0.75 mg/kg), bifeprunox (0.8 mg/kg), haloperidol (0.1 mg/kg) or vehicle three times per day for one week. The levels of protein kinase B (Akt), p-Akt, GSK3β, p-GSK3β, dishevelled (Dvl)-3, and β-catenin were measured by Western Blots. Aripiprazole increased GSK3β phosphorylation in the PFC and NAc, respectively, while haloperidol elevated it in the NAc only. However, Akt activity was not changed by any of these drugs. Additionally, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3 and β-catenin in the NAc. The present study suggests that activation of GSK3β phosphorylation in the PFC and NAc may be involved in the clinical profile of aripiprazole; additionally, aripiprazole can increase GSK3β phosphorylation via the Dvl-GSK3β-β-catenin signalling pathway in the NAc, probably due to its relatively low intrinsic activity at D2Rs.

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“…The present PPI results confirm a role for the NRG1-ErbB4 signaling pathway as a putative modulator of antipsychotic drug effects in this paradigm, as well as a target for discovery of new antipsychotic drugs. 64 , 65 …”

Section: Discussionmentioning

confidence: 99%

Specialized Information Processing Deficits and Distinct Metabolomic Profiles Following TM-Domain Disruption of Nrg1

O’Tuathaigh

Mathur

O'Callaghan

et al. 2017

Schizophrenia Bulletin

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Although there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signaling in schizophrenia. The present study focused on hitherto uncharacterized information processing phenotypes in this mutant line. Using a mass spectrometry-based metabolomics approach, we also quantified levels of unique metabolites in brain. Across 2 different sites and protocols, Nrg1 mutants demonstrated deficits in prepulse inhibition, a measure of sensorimotor gating, that is, disrupted in schizophrenia; these deficits were partially reversed by acute treatment with second, but not first-, generation antipsychotic drugs. However, Nrg1 mutants did not show a specific deficit in latent inhibition, a measure of selective attention that is also disrupted in schizophrenia. In contrast, in a “what–where–when” object recognition memory task, Nrg1 mutants displayed sex-specific (males only) disruption of “what–when” performance, indicative of impaired temporal aspects of episodic memory. Differential metabolomic profiling revealed that these behavioral phenotypes were accompanied, most prominently, by alterations in lipid metabolism pathways. This study is the first to associate these novel physiological mechanisms, previously independently identified as being abnormal in schizophrenia, with disruption of NRG1 function. These data suggest novel mechanisms by which compromised neuregulin function from birth might lead to schizophrenia-relevant behavioral changes in adulthood.

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Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

Cited by 12 publications

References 80 publications

Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies Beyond Dopamine Receptor Antagonism

Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies Beyond Dopamine Receptor Antagonism

Aripiprazole and Haloperidol Activate GSK3β-Dependent Signalling Pathway Differentially in Various Brain Regions of Rats

Specialized Information Processing Deficits and Distinct Metabolomic Profiles Following TM-Domain Disruption of Nrg1

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