Haloperidol is a potent dopamine receptor antagonist and used to treat psychotic disorders, such as schizophrenia. Recent clinical and preclinical studies demonstrated the overactivity of the nitric oxide (NO) system in schizophrenia. Neonatal ventral hippocampal (nVH) lesions in rats have been widely used as a neurodevelopmental model that mimics schizophrenia-like behaviors. Here, we investigate first whether the nVH lesion causes changes in NO levels in different limbic brain regions in young adults, postnatal day (PD) 81, and second, whether haloperidol treatment from PD60 to PD81 reverses these changes, by determining the accumulation of nitrites. The results show that NO levels at the level of the prefrontal cortex, occipital cortex, and cerebellum are higher in the nVH lesion animals, and that the haloperidol, in part, attenuates these altered NO levels. The NO levels observed in the nVH lesion animals with and without haloperidol treatment may be relevant to behaviors observed in schizophrenia.

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Dear Editor,In a recent Letter to the Editor published in this journal, Bernstein and coworkers performed a valuable integration of results obtained in his laboratory (Bernstein et al., 1999), our laboratory (Negrete-Díaz et al., 2010) and others about the role of nitric oxide (NO) in the pathophysiology of schizophrenia, and summarized them in a very comprehensive review (Bernstein et al., 2005). Using the same animal model of schizophrenia, adult rats with a neonatal ventral hippocampus (nVH) lesion, Bernstein and coworkers and our group found an alteration of the nitrergic system (an increase in the number of cortical neurons expressing neuronal nitric oxide synthase (nNOS) and NADPH diaphorase and increased production of NO respectively, in the prefrontal cortex of adult animals with nVH-lesions). Therefore, both works are complementary to each other and reinforce our view of the role of the nitrergic system in the pathophysiology of schizophrenia.The results are also consistent with postmortem studies in humans with schizophrenia, because the chronic treatment with haloperidol may produce a decrease in the expression of nNOS (see Bernstein et al., 2005 for review), and our results show that subchronic doses of the typical neuroleptic haloperidol (0.5 mg/kg) administrated to nVH-lesion animals result in a decrease of higher NO activity (Negrete-Díaz et al., 2010). This suggests that haloperidol exerts in part its therapeutic effect through its action on the activity of NO. It is interesting to note that compared to other models, the animal model of the nVH lesion is one of the best characterized, having been published to date in around a hundred works (see Tseng et al., 2009 for review). This is a neurodevelopmental model in which the behavioral changes mimic some of the symptoms of schizophrenia and are clearly observable after puberty.In summary, we believe that our findings support the integration of the results of previous works and facilitate our understanding of the role of NO in the pathophysiology of schizophrenia, as described by Bernstein and coworkers quite clearly in his letter to the editor of this journal (Bernstein et al., 2010). León-Chá vez BA, Flores G. 2010. Neonatal ventral hippocampus lesion induces increase in NO levels which is attenuated by subchronic haloperidol treatment. Synapse 64:941-947. Tseng KY, Chambers RA, Lipska BK. 2009. The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia. Behav Brain Res 204:295-305.

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