Oxytocin reduces anxiety via ERK1/2 activation: local effect within the rat hypothalamic paraventricular nucleus

TLDR

Oxytocin is a key anxiolytic neuropeptide whose central sites of action and downstream signaling pathways remain largely unknown, yet its hypothalamic effects may influence emotional regulation and therapeutic strategies for affective disorders. The study aimed to localize the anxiolytic effect of oxytocin within the hypothalamic paraventricular nucleus by bilateral microinfusion in male rats and assess behavioral outcomes in the elevated plus‑maze and light–dark box. Oxytocin activated the ERK1/2 cascade in the hypothalamus through EGF receptor‑mediated phosphorylation of Raf‑1, MEK1/2, and ERK1/2, as shown by intracerebroventricular administration and in vitro H32 neuron experiments. ERK1/2 phosphorylation was confined to paraventricular and supraoptic nucleus neurons, and inhibition of MEK1/2 abolished the PVN‑mediated anxiolytic effect, demonstrating that hypothalamic ERK1/2 signaling is causally involved and may offer therapeutic targets.

Abstract

Abstract The neuropeptide oxytocin (OT) modulates social behaviours and is an important anxiolytic substance of the brain. However, sites of action and the intracellular signalling pathways downstream of OT receptors (OTR) within the brain remain largely unknown. In the present studies, we localized the anxiolytic effect of OT by bilateral microinfusion of OT (0.01 nmol/0.5 µL) into the hypothalamic paraventricular nucleus (PVN) in male rats using both the elevated plus‐maze and the light–dark box. Moreover, intracerebroventricular administration of OT, but not of the related neuropeptide vasopressin (VP), dose‐dependently activated the extracellular signal‐regulated kinase 1/2 (ERK1/2) cascade. Specifically, OT induced the phosphorylation of Raf‐1, MEK1/2 and ERK1/2 in the hypothalamus in vivo and in hypothalamic H32 neurons via EGF receptors. OT‐induced ERK1/2 phosphorylation was immunohistochemically localized within VP neurons of the PVN and the supraoptic nucleus. Importantly, the anxiolytic effect of OT within the PVN was prevented by local inhibition of the MAP kinase cascade with a MEK1/2 inhibitor (U0126, 0.5 nmol/0.5 µL) locally infused prior to OT, indicating the causal involvement of this intracellular signalling cascade in the behavioural effect of OT. OT effects within the hypothalamus may have far‐reaching implications for the regulation of emotionality and social behaviours and, consequently, for the development of possible therapeutic strategies to treat affective disorders. Thus, OTR agonism or activation of the ERK1/2 cascade, specifically within the hypothalamus, may provide therapeutically relevant mechanisms.