New insights on nitric oxide: Focus on animal models of schizophrenia

Schizophrenia is a devastating complex disorder characterised by a constellation of behavioral deficits with the underlying mechanisms not fully known. Nitric oxide (NO) has emerged as a key signaling molecule implicated in schizophrenia. Three nitric oxide sinthases (NOS), endothelial, neuronal, and inducible, release NO within the cell. Animal models of schizophrenia are grouped in four groups, neurovedelopmental, glutamatergic, dopaminergic and genetic. In this review, we aim to evaluate changes in NO levels in animal models of schizophrenia and the resulting long-lasting behavioral and neural consequences. In particular, NO levels are substantially modified, region-specific, in various neurodevelopmental models, e.g. bilateral excitotoxic lesion of the ventral hippocampus (nVHL), maternal immune activation and direct NO manipulations early in development, among others. In regards to glutamatergic models of schizophrenia, phencyclidine (PCP) administration increases NO levels in the prefrontal cortex (PFC) and ventral hippocampus. As far as genetic models are concerned, neuronal NOS knock-out mice display schizophrenia-related behaviors. Administration of NO donors can reverse schizophrenia-related behavioral deficits. While most modifications in NO are derived from neuronal NOS, recent evidence indicates that PCP treatment increases NO from the inducible NOS isoform. From a pharmacological perspective, treatment with various antipsychotics including clozapine, haloperidol and risperidone normalize NO levels in the PFC as well as improve behavioral deficits in nVHL rats. NO induced from the neuronal and inducible NOS is relevant to schizophrenia and warrants further research.

Automated summary

Schizophrenia is a complex disorder with unknown underlying mechanisms, where nitric oxide (NO) has emerged as a key signaling molecule. Various animal models of schizophrenia show alterations in NO levels, particularly in neurodevelopmental models, glutamatergic models with PCP administration, and genetic models with neuronal NOS knock-out mice. Treatment with NO donors or antipsychotics can reverse schizophrenia-related behavioral deficits, indicating potential therapeutic implications for targeting NO in schizophrenia.