Impact of neonatal NOS-1 inhibitor exposure on neurobehavioural measures and prefrontal-temporolimbic integration in the rat nucleus accumbens

Abstract

Nitric oxide (NO) is a gaseous neurotransmitter that plays a significant role in the establishment and refinement of functional neural circuits. Genetic and post-mortem studies have suggested that neuronal NO synthase (NOS-1) activity may be compromised in frontal and temporal lobes, and related structures, in schizophrenia. The goal of this study was to determine if there is a link between neonatal disruptions in NO signalling and disturbances in the development and function of prefrontal-temporolimbic circuits. Neonatal rats were injected on postnatal days PD3-5 with the selective NOS-1 inhibitor Nω-propyl-L-arginine (NPA) and tested in adulthood (≥PD60) or as juveniles (PD30). Adult rats treated with NPA as neonates exhibited increased amphetamine-induced locomotion compared to animals receiving vehicle as neonates, whereas this was not observed in juvenile rats treated with NPA as neonates. Adult rats exposed to NPA as neonates also exhibited deficits in social interaction and short-term recognition memory, as well as reduced brain weight, compared to vehicle-treated controls. Finally, neonatal NPA exposure increased the responsiveness of nucleus accumbens neurons to prefrontal cortical input and disrupted the modulation of cortico-accumbens circuits by hippocampal afferents that is normally observed in adult animals. These results show for the first time that neonatal inhibition of NOS-1 during a critical neurodevelopmental period leads to aberrant behaviours that manifest in adulthood, as well as electrophysiological abnormalities in prefrontal-temporolimbic circuits. Greater understanding of the role of NOS-1 in the development of these circuits will shed light on how developmental insults translate to pathophysiology associated with schizophrenia.

Sodium nitroprusside is effective in preventing and/or reversing the development of schizophrenia‐related behaviors in an animal model: The SHR strain

“…Considering the long‐term preventive effect of SNP, it should also be taken into account that a disruption in nitric oxide signaling has been associated with long‐term behavioral and neuroanatomical abnormalities that might be associated with schizophrenia—see . The maturation of neurons and synaptogenesis are modulated by NO.…”

“…Improper migration of NADPH‐d, a nitric oxide synthase, neurons might lead to a disturbance in the nitrergic transmission interfering with the neurodevelopmental process culminating with the manifestation of schizophrenia later in life . In this sense, neonatal nitric oxide synthase inhibition leads to an increase in dopamine agonists‐ and stress‐induced hyperlocomotion as well as deficits in social interaction, prepulse inhibition of startle, latent inhibition, and short‐term recognition memory . In this respect, the hypertension of the SHR strain has been associated, among other factors, to a decrease of nitric oxide availability due to an increase in peripheral free radicals .…”

“…49 Considering the long-term preventive effect of SNP, it should also be taken into account that a disruption in nitric oxide signaling has been associated with long-term behavioral and neuroanatomical abnormalities that might be associated with schizophrenia-see. 50,51 The maturation of neurons and synaptogenesis are modulated by NO. Improper migration of NADPH-d, a nitric oxide synthase, neurons might lead to a disturbance in the nitrergic transmission interfering with the neurodevelopmental process culminating with the manifestation of schizophrenia later in life.…”

“…51 In this sense, neonatal nitric oxide synthase inhibition leads to an increase in dopamine agonists-and stress-induced hyperlocomotion as well as deficits in social interaction, prepulse inhibition of startle, latent inhibition, and short-term recognition memory. [50][51][52][53] In this respect, the hypertension of the SHR strain has been associated, among other factors, to a decrease of nitric oxide availability due to an increase in peripheral free radicals. 54 The same decrease in nitric oxide availability due to an increase in oxidative stress might occur in the central ner- alterations in the nitrergic system, increased brain oxidative stress, and neuroinflammation have been described in the SHR strain 19,20,23,24 and might underlie the beneficial effect of SNP presented here.…”

Role of nitric oxide and related molecules in schizophrenia pathogenesis: biochemical, genetic and clinical aspects

“…The decreased synthesis of nitric oxide in the brain is also discussed as a pathogenic factor of mental disorders. It has been shown that nNOS deficiency in experiments results in cognitive and behavioral disturbances, pathognomonic for schizophrenia (Kirchner et al, 2004 ; Dec et al, 2014 ). Therefore, even the migration of neurons described above may result in NO deficit in some areas and in cognitive deficiency.…”