Abstract
The nitric oxide (NO) pathway in the brain is involved in response to psychosocial stressors. The aim of this study was to elucidate the role of nNOS and iNOS in the prefrontal cortex (PFC), hippocampus (HIP), and hypothalamus (HYPO) during social isolation stress (IS), social crowding stress (CS), and a combined IS + CS. In the PFC, 3 days of CS increased iNOS but not nNOS protein level. In the HIP and HYPO, the levels of nNOS and iNOS significantly increased after 3 days of CS. In the PFC, IS alone (11 days) enhanced iNOS protein level following 3 days of CS and increased nNOS level in the HIP and HYPO after 14 days of CS. By contrast, in the HIP, IS abolished the subsequent CS-induced increase in nNOS in the HIP and strongly elevated iNOS level after 7 days of CS. In the HYPO, prior IS inhibited nNOS protein level induced by subsequent CS for 3 days, but increased nNOS protein level after longer exposure times to CS. Isolation stress strongly upregulated plasma interleukin-1β (IL-1β) and adrenocorticotropic hormone (ACTH) levels while corticosterone (CORT) level declined. We show that the modulatory action of the NO pathway and ACTH/CORT adaptation to chronic social isolation stress is dependent on the brain structure and nature and duration of the stressor. Our results indicate that isolation is a robust natural stressor in social animals; it enhances the NO pathway in the PFC and abolishes subsequent social CS-induced NOS responses in the HIP and HYPO.
Highlights
The activation of the hypothalamic-pituitary-adrenal (HPA) axis is widely accepted as one of the central physiologicalNeurotox Res (2019) 36:523–539 mechanisms involved in the stress response
Blots containing proteins were exposed to the following antibodies: primary rabbit anti-nNOS (1:400, sc-648) and anti-Inducible type NOS (iNOS) (1:400, sc-650), polyclonal antibodies, primary mouse anti-β-actin (1:400, sc-47778), monoclonal antibody followed by goat anti-rabbit (1:10000, sc-2004), and goat anti-mouse (1:4000, sc-648) horseradish peroxidase– conjugated secondary antibodies, all of which were provided by Santa Cruz Biotechnology, Dallas, TX, USA
We observed that iNOS protein expression significantly increased in the prefrontal cortex (PFC) but not in the HIP or HYPO, suggesting that the iNOS/nitric oxide (NO) pathway is almost selectively activated in the PFC during central adaptation to chronic stimulation during severe psychosocial isolation stress (IS)
Summary
The activation of the hypothalamic-pituitary-adrenal (HPA) axis is widely accepted as one of the central physiologicalNeurotox Res (2019) 36:523–539 mechanisms involved in the stress response. The most adapting changes induced by chronic stress are observed in the hippocampus (HIP) and PFC—brain regions which play a role in mediating the effects of stress on the regulation of glucocorticoids (GCs) in rats similar to those observed in people with psychiatric disorders, including depression (Filipović et al 2017). Neuronal NOS activation by acute restraint stress plays a prominent role in local nitrergic neurotransmission in the hypothalamic paraventricular nucleus (PVN) while having a facilitatory influence on the delayed emotional consequences of stress (Busnardo et al 2019). Nitric oxide generated by nNOS can act as a neurotransmitter (Guix et al 2005) It is involved in the cholinergic stimulation of the HPA axis response during psychosocial crowding stress (CS) (Bugajski et al 2006). Acute stressors are known to increase nNOS, but not iNOS protein expression in the PFC (Zlatković and Filipović 2013)
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