Abstract
The c-Raf – MEK1/2 – ERK1/2 mitogen-activated protein kinase (MAPK) intracellular signalling cascade in neurons plays important roles in the control of a variety of behaviours, including social behaviours and anxiety. These roles partially overlap with those described for oxytocin (OXT), and it has been shown that OXT activates the MAPK pathway in the hypothalamus (of male), and hippocampus (of female) rats. Here, by combining behavioural (light/dark box) and biochemical analyses (western blotting), we tested two hypotheses: (i) that OXT is anxiolytic within the hypothalamus of females, and (ii) that this effect, as well as that of lactation-associated anxiolysis, depends on the recruitment of the MAPK pathway. We found that, when injected bilaterally into the hypothalamic paraventricular nucleus (PVN), OXT decreased anxiety-like behaviour in virgins, and that this effect depended on phosphorylation of MEK1/2. MAPK pathway activation in lactation was evident by high phosphorylated (p) MEK1/2 levels, and nuclear translocation of ERK1. The high pMEK1/2 levels were necessary for the anxiolytic phenotype typically observed during lactation. Interestingly, exogenous OXT in lactating rats reduced pMEK1/2 levels without a concomitant effect on anxiety, indicating that OXT receptor activation can lead to recruitment of additional intracellular pathways to modulate MEK activity. Still other pathways could include MEK, but without subsequent activation of ERK, as we did not observe any increase in OXT-induced ERK phosphorylation. Together the results demonstrate that the MAPK pathway, especially MEK1/2, is critically involved in the regulation of anxiety-like behaviour in female rats.
Highlights
The c-Raf – MEK1/2 – ERK1/2 mitogen-activated protein kinase (MAPK) pathway is one of the most important and beststudied intracellular signalling pathways
These effects overlap, at least partially, with those reported for the neuropeptide oxytocin (OXT), and it has been shown that OXT activates the MAPK pathway within the hypothalamic paraventricular nucleus (PVN) via transactivation of the epidermal growth factor receptor (EGFR) to regulate anxiety in male rats [3]
ANOVA did not reveal a significant effect of either bilateral infusion of U0126 (F1,29 = 2.21; p = 0.15) or OXT (F1, 29 = 3.59; p = 0.068) directly into the PVN on the relative time spent in the light box of the light dark box (LDB)
Summary
The c-Raf – MEK1/2 – ERK1/2 mitogen-activated protein kinase (MAPK) pathway is one of the most important and beststudied intracellular signalling pathways. ERKs have been shown to regulate anxiety-like behaviour and to contribute to the control of social behaviours, including social memory and aggression, via ERK2 [2]. These effects overlap, at least partially, with those reported for the neuropeptide oxytocin (OXT), and it has been shown that OXT activates the MAPK pathway within the hypothalamic paraventricular nucleus (PVN) via transactivation of the epidermal growth factor receptor (EGFR) to regulate anxiety in male rats [3]. It has been repeatedly demonstrated that exogenous central administration of AVP has an anxiogenic effect [5] and that its expression level within the PVN negatively correlates with anxiety-related behaviour [6,7]
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