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

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 microL) 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 microL) 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.

Oxytocin Stimulates Extracellular Ca2+ Influx Through TRPV2 Channels in Hypothalamic Neurons to Exert Its Anxiolytic Effects

“…OXT was infused at 0.01 nmol/0.5 μl per PVN to induce anxiolysis (Blume et al, 2008). The concentration of SKF96365 (0.5 nmol/0.5 μl) was selected following testing of several doses, while monitoring any signs of tremor, convulsions, wet-dog shakes, or grooming in the homecage.…”

“…For intra-PVN infusions, indwelling bilateral guide cannulae (stainless steel, 23G, 12-mm long) were implanted 2 mm above both the left and the right PVN (AP: − 1.4 mm bregma, ML: − 1.8 and +2.1 mm lateral; DV: +6 mm below the surface of the skull; angle 10°; Blume et al, 2008), and were anchored to two stainless-steel screws using dental acrylic. The guide cannulae were kept viable with dummy cannulae, which were removed daily and cleaned during the handling procedure.…”

“…It is released into the circulation to control peripheral physiological parameters (Gimpl and Fahrenholz, 2001), and also centrally from dendrites of magnocellular neurons (Ludwig et al, 2002) and from axons that target a variety of brain regions (Knobloch et al, 2012). Central OXT facilitates pro-social behaviors including pair-bonding and social preference (Lukas et al, 2008), and is anxiolytic in the amygdala (Bale et al, 2001) and PVN (Blume et al, 2008), but anxiogenic in the lateral septum (Guzman et al, 2013).…”

“…One of these pathways involves transactivation of the epidermal growth factor receptor (EGFR), followed by the activation by phosphorylation of the mitogen-activated protein kinase kinase (MEK1/2). Phosphorylated MEK1/2 (pMEK1/2) mediates the anxiolytic activity of OXT in the PVN, in both male and female rats (Blume et al, 2008).…”

A Candidate Circuit Approach to Investigating Autism

“…Consistent with a role for PI3K signaling in these cell types, phosphomTOR is enriched in the adult rat PVN (Cota et al, 2006). There is also evidence from mice that oxytocin acts via the mitogen-activated protein kinase (MAPK) pathway in the PVN to mediate anxiolytic effects (Blume et al, 2008). MAPK signaling is implicated in ASD, because the gene MAPK3 is located in the 16p11.2 deletion region, which is a risk factor for ASD (Weiss et al, 2008).…”