The International Journal of Neuropsychopharmacology

Research Article

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

Alexander M. Deca1, Kathy L. Kohlhaasa2, Christopher L. Nelsona1, Kristina E. Hoquea1, Solmaz N. Leilabadia1, Jessica Folka1, Marina E. Wolfa1 and Anthony R. Westa1 c1

a1 Department of Neuroscience, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA

a2 Neuroscience Research, Global Research and Development, Abbott Laboratories, 100 Abbott Park Rd, Abbott Park, IL 60064-6115, USA

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 N ω -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.

(Received June 18 2013)

(Reviewed July 12 2013)

(Revised July 27 2013)

(Accepted August 07 2013)

(Online publication September 12 2013)

Key words

  • Hippocampus;
  • nucleus accumbens;
  • prefrontal cortex;
  • schizophrenia

Correspondence

c1 Address for correspondence: Dr A. R. West, Department of Neuroscience, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd, North Chicago, IL 60064, USA. Tel.: (847) 578-8658 Fax: (847) 578-8515 Email: Anthony.West@rosalindfranklin.edu