Unknown,Transcriptomics,Genomics,Proteomics

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Unique pharmacological actions of atypical neuroleptic quetiapine: possible role in cell cycle/fate control

ABSTRACT: Quetiapine is an atypical neuroleptic with a pharmacological profile distinct from classic neuroleptics. It is currently approved for treating patients with schizophrenia, major depression and bipolar I disorder. However, its cellular effects remain elusive. We used microarrays to characterize RNA transcript levels in the brains of mice chronically treated with quetiapine, the neuroleptic haloperidol, or vehicle. We further characterized particular RNA transcripts in cortical cell cultures. Mice were given one of 5 treatments (vehicle, 1 mg/kg haloperidol, 0.3 mg/kg haloperidol, 100 mg/kg quetiapine, 10 mg/kg quetiapine). Pooled tissue samples were used for microarray analysis of gene expression in the frontal cortex (FC) and striatum (STR). Frontal cortex gene targets were subsequently verified with quantitative real-time PCR (qRT-PCR) from the same cohort of mice and an independent cohort.

ORGANISM(S): Mus musculus

SUBMITTER: Jonathan Pevsner

PROVIDER: E-GEOD-45229 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Unique pharmacological actions of atypical neuroleptic quetiapine: possible role in cell cycle/fate control.

Kondo M A MA Tajinda K K Colantuoni C C Hiyama H H Seshadri S S Huang B B Pou S S Furukori K K Hookway C C Jaaro-Peled H H Kano S-i SI Matsuoka N N Harada K K Ni K K Pevsner J J Sawa A A

Translational psychiatry 20130402

Quetiapine is an atypical neuroleptic with a pharmacological profile distinct from classic neuroleptics that function primarily via blockade of dopamine D2 receptors. In the United States, quetiapine is currently approved for treating patients with schizophrenia, major depression and bipolar I disorder. Despite its widespread use, its cellular effects remain elusive. To address possible mechanisms, we chronically treated mice with quetiapine, haloperidol or vehicle and examined quetiapine-specif ...[more]

PMID: 23549417

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Project description:Schizophrenia is a chronic mental illness that is among the world’s top twenty causes of years lost to disability according to the global burden of disease 2019 (10.1016/S0140-6736(20)30925-9). Positive symptoms, including hallucinations and delusions in schizophrenia, often improved with conventional antipsychotic medication, which exerts its therapeutic effects mainly by antagonizing the dopamine D2 receptors. Haloperidol was one of the first antipsychotics to be approved by the FDA, and it is since then widely used for the treatment of psychotic disorders including schizophrenia. Despite its high affinity for dopamine D2 receptors, it has been shown that haloperidol interacts with other receptors, such as dopamine D3 and D4 receptors, α-adrenergic receptor 1 and to some extent 5HT2A. Dopaminergic dysfunction is known for decades to be involved in the pathophysiology of schizophrenia, but only recently has the striatum been implicated in such devasting disorder. The dorsal striatum is a brain region involved in motor, cognitive and motivational functions, highly impacted by antipsychotic drugs. Particularly, it is well-recognized that chronic haloperidol administration has a tremendous impact on striatal synaptic plasticity, by changing the volume of dorsal striatum, the number of striatal neurons and the synaptic morphology, both in humans and rodents. Despite the overwhelming evidence correlating chronic haloperidol administration with striatum alterations, so far, the exact striatal synaptic mechanism by which haloperidol exerts its beneficial effects remains unclear. Although dopamine D2 receptor blockade can be achieved within hours after haloperidol administration, the onset of action is delayed by weeks. Thus, it is crucial to better understand the neuronal mechanism behind the delayed clinical effects of haloperidol to improve the treatment outcome. Using proteomic analysis and whole-cell patch-clamp recordings (Figure 1), we demonstrate for the first time a possible mechanism by which haloperidol may be contributing to its beneficial long-term therapeutic effect. Specifically, we demonstrate that modulation of D2-MSNs by chronic haloperidol administration leads to a slow remodeling of D1-neurons that may be responsible for its positive therapeutic effects.

Dataset Information

Unique pharmacological actions of atypical neuroleptic quetiapine: possible role in cell cycle/fate control

Publications

Unique pharmacological actions of atypical neuroleptic quetiapine: possible role in cell cycle/fate control.

Similar Datasets

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