Abstract
An increasing amount of research aims at recognizing the molecular mechanisms involved in long-lasting brain architectural changes induced by antipsychotic treatments. Although both structural and functional modifications have been identified following acute antipsychotic administration in humans, currently there is scarce knowledge on the enduring consequences of these acute changes. New insights in immediate-early genes (IEGs) modulation following acute or chronic antipsychotic administration may help to fill the gap between primary molecular response and putative long-term changes. Moreover, a critical appraisal of the spatial and temporal patterns of IEGs expression may shed light on the functional “signature” of antipsychotics, such as the propensity to induce motor side effects, the potential neurobiological mechanisms underlying the differences between antipsychotics beyond D2 dopamine receptor affinity, as well as the relevant effects of brain region-specificity in their mechanisms of action. The interest for brain IEGs modulation after antipsychotic treatments has been revitalized by breakthrough findings such as the role of early genes in schizophrenia pathophysiology, the involvement of IEGs in epigenetic mechanisms relevant for cognition, and in neuronal mapping by means of IEGs expression profiling. Here we critically review the evidence on the differential modulation of IEGs by antipsychotics, highlighting the association between IEGs expression and neuroplasticity changes in brain regions impacted by antipsychotics, trying to elucidate the molecular mechanisms underpinning the effects of this class of drugs on psychotic, cognitive and behavioral symptoms.
Highlights
There is growing interest in unraveling the cellular mechanisms putatively involved in long-term changes in brain architecture and function following antipsychotic administration (Ahmed et al, 2008; Ho et al, 2011; Cannon et al, 2015; Vita et al, 2015; Yue et al, 2016; Emsley et al, 2017)
We carried out multiple searches on Pubmed, Scopus, and ISI Web of Knowledge using as a reference the following keywords: Immediate Early Genes AND brain (2335); Immediate Early Genes AND antipsychotics (84); Immediate early genes AND antipsychotics AND brain (74)
Antipsychotic agents are the mainstay of treatment in schizophrenia and in other psychotic disorders
Summary
There is growing interest in unraveling the cellular mechanisms putatively involved in long-term changes in brain architecture and function following antipsychotic administration (Ahmed et al, 2008; Ho et al, 2011; Cannon et al, 2015; Vita et al, 2015; Yue et al, 2016; Emsley et al, 2017). New insights in IEGs expression following acute or chronic antipsychotic administration in preclinical models may help to fill the gap between primary molecular responses to antipsychotic administration and putative long-term synaptic changes (Figure 1). Multiple lines of evidence demonstrated that in vivo antipsychotic treatment may significantly impact the architecture of the synapse, as well as the re-arrangement of gene expression of scaffolding and adaptor proteins after acute exposure to the drugs. In line with this view, haloperidol acute administration has been shown to reduce dendritic spines size, possibly through a beta-adducin-mediated mechanism (Engmann et al, 2016). We will consider: 1) How IEGs induction may impact directly or indirectly synaptic architecture; 2) How IEGs are differentially affected by acute and chronic antipsychotic treatment; 3) How antipsychotics with different receptor profile or the same antipsychotic at different doses may affect the expression of different IEGs with regard of brain topography
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