Re-arrangements of glutamatergic post-synaptic density transcripts after antipsychotics and add-on compounds administration in preclinical settings: translational implications for psychosis therapy and treatment resistance

Abstract

The possibility to translate real-world practice treatment strategies in psychosis to preclinical settings gives the opportunity to dissect at a molecular level the putative modifications that occur and concur to synaptic plasticity rearrangements. Dopamine-glutamate interplay dysfunctions have been suggested as key factors in psychosis pathophysiology and for the most part, synaptic interactions between dopamine and glutamate signaling pathways take part at the post-synaptic density (PSD). Therefore, the major goal of the present research was to focus on PSD adaptations to pharmacological manipulations mimicking common clinical situations. According to these premises, here we provide a set of preclinical studies whose aim was to investigate: i) the postsynaptic molecular adaptations to prolonged pharmacological treatments with the specific scope of comparing novel multitargeting agents to first and second generation antipsychotics currently used in clinical practice; ii) the comparison of acute versus chronic plasticity-related genes differences in terms of expression as a molecular fingerprint of the two different treatment situations; iii) the molecular effects on key PSD molecules of the combined assumption of voluptuary substances such as caffeine and nicotine plus antipsychotics; iv) the adaptations of PSD transcripts to novel proposed add-on treatment options to antipsychotics, and particularly to the administration of minocycline. With the first set of experiments, particular efforts were made at recreating current pharmacological strategies focusing on newly approved antipsychotic agents that may activate postsynaptic transcripts with a different topographic distribution from that elicited by standard therapies, and that may suggest better clinical efficacy or possibly some new adverse effects. This study was followed by the second set of experiments with the specific aim of providing a direct head-to-head comparison of the synaptic molecular changes caused by acute versus chronic administration of the same compounds focusing on the IEG Homer1a. The third set of experiments, through topographic analyses and a behavioral study, was aimed at providing the differential region-specific brain gene expression changes that may occur when antipsychotics are taken with nicotine and caffeine, whose positive or negative additive effects are still a matter of debate at the clinical level. Finally, since glutamatergic agents have been considered as potentially relevant add-on strategies to antipsychotics in order to reduce negative symptoms and improve cognition, the last set of experiments was aimed at dissecting the molecular effects of the synthetic second-generation tetracycline minocycline that has been recently suggested for the treatment of schizophrenia. Indeed, several lines of evidence suggest that this antibiotic may exert glutamatergic modulatory and anti-inflammatory effects, which are consistent with a potential implication of inflammatory and oxidative pathways in the pathophysiology of psychosis