Chronic treatment with the antipsychotic drug blonanserin modulates the responsiveness to acute stress with anatomical selectivity

Patients diagnosed with schizophrenia typically receive life-long treatments with antipsychotic drugs (APDs). However, the impact of chronic APDs treatment on neuroplastic mechanisms in the brain remains largely elusive. Here, we focused on blonanserin, a second-generation antipsychotic (SGA) that acts as an antagonist at dopamine D2, D3, and serotonin 5-HT2A receptors, and represents an important tool for the treatment of schizophrenia. We used rats to investigate the ability of chronic treatment blonanserin to modulate the activity of brain structures relevant for schizophrenia, under baseline conditions or in response to an acute forced swim session (FSS). We measured the expression of different immediate early genes (IEGs), including c-Fos, Arc/Arg 3.1, Zif268 and Npas4. Blonanserin per se produced limited changes in the expression of these genes under basal conditions, while, as expected, FSS produced a significant elevation of IEGs transcription in different brain regions. The response of blonanserin-treated rats to FSS show anatomical and gene-selective differences. Indeed, the upregulation of IEGs was greatly reduced in the striatum, a brain structure enriched in dopamine receptors, whereas the upregulation of some genes (Zif268, Npas4) was largely preserved in other regions, such as the prefrontal cortex and the ventral hippocampus. Taken together, our findings show that chronic exposure to blonanserin modulates selective IEGs with a specific anatomical profile. Moreover, the differential activation of specific brain regions under challenging conditions may contribute to specific clinical features of the drug.