Almost 25% of schizophrenia patients suffer from obsessive-compulsive symptoms (OCS) considered a transdiagnostic clinical continuum. The presence of symptoms pertaining to both schizophrenia and obsessive-compulsive disorder (OCD) may complicate pharmacological treatment and could contribute to lack or poor response to the therapy. Despite the clinical relevance, no reviews have been recently published on the possible neurobiological underpinnings of this comorbidity, which is still unclear. An integrative view exploring this topic should take into account the following aspects: (i) the implication for glutamate, dopamine, and serotonin neurotransmission as demonstrated by genetic findings; (ii) the growing neuroimaging evidence of the common brain regions and dysfunctional circuits involved in both diseases; (iii) the pharmacological modulation of dopaminergic, serotoninergic, and glutamatergic systems as current therapeutic strategies in schizophrenia OCS; (iv) the recent discovery of midbrain dopamine neurons and dopamine D1- and D2-like receptors as orchestrating hubs in repetitive and psychotic behaviors; (v) the contribution of N-methyl-D-aspartate receptor subunits to both psychosis and OCD neurobiology. Finally, we discuss the potential role of the postsynaptic density as a structural and functional hub for multiple molecular signaling both in schizophrenia and OCD pathophysiology.

Background: Antipsychotic agents modulate key molecules of the postsynaptic density (PSD), including the Homer1a gene, implicated in dendritic spine architecture. How the antipsychotic receptor profile, dose, and duration of administration may influence synaptic plasticity and the Homer1a pattern of expression is yet to be determined. Methods: In situ hybridization for Homer1a was performed on rat tissue sections from cortical and striatal regions of interest (ROI) after acute or chronic administration of three antipsychotics with divergent receptor profile: Haloperidol, asenapine, and olanzapine. Univariate and multivariate analyses of the effects of topography, treatment, dose, and duration of antipsychotic administration were performed. Results: All acute treatment regimens were found to induce a consistently higher expression of Homer1a compared to chronic ones. Haloperidol increased Homer1a expression compared to olanzapine in striatum at the acute time-point. A dose effect was also observed for acute administration of haloperidol. Conclusions: Biological effects of antipsychotics on Homer1a varied strongly depending on the combination of their receptor profile, dose, duration of administration, and throughout the different brain regions. These molecular data may have translational valence and may reflect behavioral sensitization/tolerance phenomena observed with prolonged antipsychotics.

Although antipsychotics’ mechanisms of action have been thoroughly investigated, they have not been fully elucidated at the network level. We tested the hypothesis that acute pre-treatment with ketamine (KET) and administration of asenapine (ASE) would modulate the functional connectivity of brain areas relevant to the pathophysiology of schizophrenia, based on transcript levels of Homer1a, an immediate early gene encoding a key molecule of the dendritic spine. Sprague–Dawley rats (n = 20) were assigned to KET (30 mg/kg) or vehicle (VEH). Each pre-treatment group (n = 10) was randomly split into two arms, receiving ASE (0.3 mg/kg), or VEH. Homer1a mRNA levels were evaluated by in situ hybridization in 33 regions of interest (ROIs). We computed all possible pairwise Pearson correlations and generated a network for each treatment group. Acute KET challenge was associated with negative correlations between the medial portion of cingulate cortex/indusium griseum and other ROIs, not detectable in other treatment groups. KET/ASE group showed significantly higher inter-correlations between medial cingulate cortex/indusium griseum and lateral putamen, the upper lip of the primary somatosensory cortex, septal area nuclei, and claustrum, in comparison to the KET/VEH network. ASE exposure was associated with changes in subcortical-cortical connectivity and an increase in centrality measures of the cingulate cortex and lateral septal nuclei. In conclusion, ASE was found to finely regulate brain connectivity by modelling the synaptic architecture and restoring a functional pattern of interregional co-activation.