Transcriptomic analyses of rats exposed to chronic mild stress: Modulation by chronic treatment with the antipsychotic drug lurasidone

Exposure to stressful experiences accounts for almost half of the risk for mental disorders. Hence, stress-induced alterations represent a key target for pharmacological interventions aimed at restoring brain function in affected individuals. We have previously demonstrated that lurasidone, a multi-receptor antipsychotic drug approved for the treatment of schizophrenia and bipolar depression, can normalize the functional and molecular impairments induced by stress exposure, representing a valuable tool for the treatment of stress-induced mental illnesses. However, the mechanisms that may contribute to the therapeutic effects of lurasidone are still poorly under-stood. Here, we performed a transcriptomic analysis on the prefrontal cortex (PFC) of adult male rats exposed to the chronic mild stress (CMS) paradigm and we investigated the impact of chronic lurasidone treatment on such changes. We found that CMS exposure leads to an anhedonic phenotype associated with a down-regulation of different pathways associated to neuronal guidance and synaptic plasticity within the PFC. Interestingly, a significant part of these alterations (around 25%) were counteracted by lurasidone treatment. In summary, we provided new insights on the transcriptional changes relevant for the therapeutic intervention with lurasidone, which may ultimately promote resilience.

Automated summary

Exposure to stressful experiences is a significant risk factor for mental disorders, and pharmacological interventions targeting stress-induced alterations can help restore brain function. Lurasidone, an antipsychotic drug, has been shown to normalize the impairments caused by stress exposure and could be a valuable treatment for stress-induced mental illnesses. However, the mechanisms underlying the therapeutic effects of lurasidone are not well understood. This study found that chronic lurasidone treatment counteracted some of the transcriptional changes induced by chronic mild stress exposure, providing new insights into the potential therapeutic effects of lurasidone.