Spatial and temporal patterns of postsynaptic genes and proteins expression by multiple receptors targeting agents: unraveling the impact of multitargeting approach on dopamine-glutamate mediated synaptic plasticity

Dysfunctions in the interplay among multiple neurotransmitter systems have been implicated in the pathophysiology of major psychiatric disorders, such as schizophrenia, bipolar disorder or major depression, which display a wide range of behavioral, emotional and cognitive alterations. Particularly, schizophrenia is a highly complex and multidimensional disorder, which shows a large number of unmet needs in terms of positive, negative and cognitive symptoms control in patients by current available pharmacotherapy. Indeed, an extimated 30% of patients do not satisfactorily respond to present treatments, and only a small percentage of responding patients is able to restart a normal working life. Thus, the complex clusters of symptoms showed by schizophrenic patients often need more than one psychiatric drug from the same or a different pharmacological class, particularly under the following conditions: 1) when monotherapy provides insufficient improvement of the core symptoms; 2) when there are concurrent additional symptoms requiring more than one class of medications; 3) to improve tolerability, by using two compounds under dose thresholds to limit side effects. Currently, the choice of antipsychotic combinations is based on empirical paradigms guided by clinical responses. Some empirically-supported antipsychotic combination therapies include the following: 1) the combination of atypical antipsychotics with other atypical or typical antipsychotics in clozapine-refractory schizophrenia; 2) the addition of antipsychotics to mood stabilizers for acute mania or for maintenance in bipolar disorder [152]; 3) the addition of antipsychotics to antidepressants in treatment-resistant major depression or in psychotic depression, as well as the addition of antidepressants to antipsychotics to control prominent negative symptoms in chronic schizophrenia.Although still dearth at present, data from preclinical studies suggest that combined therapies may induce molecular changes that are sharply different, and often synergistic, as compared to those induced by individually administered drugs. For instance, several studies describe a specific impact of antipsychotic-SSRI combination treatment on the expression of immediate-early genes and neurotrophic factors, different from that obtained by the administration of each drug alone. Moreover, preclinical studies have also demonstrated that both mood stabilizers and antipsychotics may impact common intracellular target molecules that are involved in the transductional pathways of dopamine signaling (i.e. AKT/GSK-3 pathway, MAP kinases pathway, postsynaptic density proteins). Finally, new multitargeting drugs, such as asenapine, have been demonstrated to concurrently impact different neurotransmission systems, which may crosslink at crucial steps along neural transductional pathways, thereby synergistically reinforce downstream signaling in selected brain areas deputed to control cognitive and behavioral functions. These observations support the hypothesis that convergence at crucial steps of intracellular dopaminergic pathways could be responsible for synergistic effects obtained by the co-administration of apparently heterogeneous compounds. Understanding the biological mechanisms by which combined and multitargeting treatments act could enable a targeted selection of drugs, as well as provide further insights into the pathophysiology of neuropsychiatric symptoms . Here we provide a set of preclinical studies whose aim was to investigate the postsynaptic molecular responses to either combined treatment strategies or novel multitargeting agents currently used in psychiatric clinical practice. First aim was to evaluate whether combined treatments may impact differentially postsynaptic genes/proteins as compared to treatments individually administered. With regards to multitargeting agents, we compared them to “older” antipsychotics in order to evaluate the different impact on postsynaptic molecules. Second goal was to determine whether combined strategies or multitargeting agents may activate postsynaptic transcripts in brain areas that are different from that elicited by standard therapies, and that may suggest better clinical efficacy on some cluster symptoms, or possibly some new adverse effects. Through topographic analysis, we aimed at providing imagines of this differential region-specific brain gene expression by the distinct compounds evaluated. Finally, we aimed at investigating if the different gene/protein modulation by agents administered was elicited in functionally correlated brain areas and whether animal behavior responses may relate to such a selective cortical-subcortical integrated postsynaptic molecules modulation.