Schizophrenia and the nitric oxide controversy: Do all things fall into place now?

Dear Editor, The purpose of this Letter to the Editor is to commend Dr. Negrete-Dı́az and coworkers for a particular aspect of their interesting investigation reported in Synapse (Negrete-Dı́az et al., 2010). In their study, they report two major results: (1) elevated levels of nitric oxide (NO) are measurable in different brain regions of adult rats with neonatal ventral hippocampus (nVH) lesion and (2) long-term treatment of these animals with subchronic doses of the typical neuroleptic haloperidol attenuates these alterations in brain NO production. Although there is no doubt about the prominent involvement of the nitrergic system in schizophrenia, it is less clear whether an increased or a decreased NO generation is typical of the disease (summarized in Bernstein et al., 2005). Findings of Negrete-Dı́az et al. pointing to an elevated generation of NO in a well-established animal model of schizophrenia are in good accordance to our previous findings on the expression of neuronal nitric oxide synthase (nNOS)/NADPH diaphorase in VH-lesioned rats (Bernstein et al., 1999). We could show that, compared with sham-operated rats and animals who received an ibotenic acid induced VH destruction as adults, in nVHlesioned rats there is a significant increase of nNOS and NADPH diaphorase expressing neurons in the medial prefrontal cortex and the peri/entorhinal cortex, but not in the nuc. accumbens. Negrete-Dı́az and coworkers also provide some evidence that the main cellular source of the elevated NO levels in nVH rats are neurons (and not endothelia or microglial cells). Hence, nNOS must be regarded the principal NO-generating enzyme in these experiments. Moreover, increased NO levels were detected in such brain areas, where we found at that time an elevated expression of the NO-generating enzyme nNOS (prefrontal and temporal cortex). Of particular importance for our understanding of the role of NO in schizophrenia is the revealed ‘‘NO-normalizing’’ effect of haloperidol (although the dosage used by Negrete-Dı́az et al. is fairly high). In a series of biochemical and histochemical post-mortem brain studies on nNOS expression in chronic schizophrenia, published from our and other laboratories, a decreased expression of nNOS was found (for review, see Bernstein et al., 2005). Of note, a vast majority of schizophrenic patients included in these studies had received long-term treatment with haloperidol. Given the ‘‘NO-reducing’’ effect of this antipsychotic at therapeutic doses, the decreased expression of nNOS in post mortem human brains of schizophrenics might well be the consequence of neuroleptic administration and not reflect the original diseaserelated situation. As a certain limitation, it should be emphasized, however, that animal models of schizophrenia do not completely mimic all aspects of the human disease. Hence, it is not fully clear, if elevated NO levels as measured in nVH-lesioned rats permit to conclude that a similar activation of the nitrergic system must happen in humans, too. Further, a reduction of NOS-expressing hippocampal neurons was found in another schizophrenia model, the ketamine paradigm (Keilhoff et al., 2004), where the animals had no contact with haloperidol or other neuroleptics. In sum, the interesting findings of Negrete-Dı́az and coworkers are a valuable contribution to the long-lasting discussion about the impact of NO on schizophrenia.