Modulation of neurotrophic mechanisms and glutamate signalling after chronic treatment with the novel antipsychotic lurasidone in rats

Objective The therapeutic activity of antipsychotic drugs (APDs) depends on their interaction with different neurotransmitter receptors, which leads to the control of specific symptoms of schizophrenia. However, it is now generally accepted that neuroadaptive changes taking place following repeated administration of APDs may be relevant for long-term stabilization and for the improvement of depressive symptoms and cognitive deficits, that are probably linked to complex cellular mechanisms impinging on neuronal plasticity. To this extent, it is important to examine long-term changes set in motion by APD treatment in order to identify novel systems and pathways that may contribute to their therapeutic activity. Methods We treated male Sprague Dawley rats for 21 days with vehicle or lurasidone (10 mg/kg) and investigated gene and protein expression changes in hippocampus and prefrontal cortex, focusing on the neurotrophin BDNF, its high affinity receptor TrkB as well as AMPA and NMDA glutamate receptor subunits. Results We found that chronic lurasidone treatment increases the expression of BDNF in rat prefrontal cortex and produces a significant down-regulation of the truncated form for its high affinity receptor TrkB. These changes may be suggestive of enhanced neuronal plasticity that can sustain functions, such as cognition, associated with this brain structure. With regard to the glutamatergic system, chronic treatment with lurasidone did not produce any major change in the levels of AMPA and NMDA receptor subunits measured in post-synaptic densities, a difference from the first generation APD haloperidol that has a marked negative impact on glutamatergic synapses (Fumagalli et al., Molecular Pharmacology, 2008). Conclusion Our data suggest that neuroplastic changes produced after repeated treatment with lurasidone in brain structures, such as the prefrontal cortex, may contribute to the amelioration of symptomatic and functional deficits found in patients with schizophrenia