Evidence that vasopressin exerts influence through the V1b receptor in the hippocampus during acute models of inflammation and neuroinflammation

Nicholas Buss1,2, Andrea Terron1, Julia Buckingham2. 1GlaxoSmithKline, Verona, Italy, 2Imperial College, London, United Kingdom.

Arginine vasopressin (AVP), exerts multiple physiological actions e.g. pressor and anti-diuretic functions, that are considered to be mediated through three GPCR sub-types: AVPr1a, AVPr1b (V1b) and AVPr2. Within the HPA-axis, CRH and AVP respond rapidly to an acute stressor to release ACTH, and following chronic stress there is a reduction of CRH and an increase in AVP(1). Of the three receptors, V1b has been localised to the anterior pituitary gland and is also widely distributed in the CNS, including the hippocampus, in which it has recently been suggested that AVP may potentiate hippocampal synaptic plasticity(2, 3).

This study investigates the HPA-axis following peripherally (HPA-activation) or centrally (neuroinflammation) administered LPS in C57Bl/6 male mice (ca. 11 weeks old). The presence of mRNA for V1b in the brain from untreated mice (n=6) was evaluated using in situ hybridisation (ISH) with diverse 33P labelled antisense probes. The brain and pituitary gland were then collected (0, 2, 4, 8 and 24h) after induction of different acute inflammatory stressors administered either peripherally (LPS, 500µg/kg i.p., n=6) or centrally (LPS, 50µg/kg i.c.v., n=6) and TaqMan® Real-Time RT-PCR for V1b, with β-actin β-microglobulin and GAPDH as housekeeping genes for normalisation was performed. Untreated and saline treated (2.5 ml/kg, i.p. or 50µl/kg, i.c.v.) control animals were studied in parallel. Evaluation of the brain using ISH showed a strong signal for V1b mRNA in the hippocampus only on coronal brain sections from untreated mice (n=6) following ISH. No changes in V1b were seen in the hypothalamus or pituitary gland 2-24h after i.p. administration of LPS. By contrast, peripheral administration of LPS caused significant decrease in V1b mRNA in the hippocampus after 2h (23%, p<0.05) compared with time-matched saline controls. Following i.c.v. administration of LPS there were no changes in the expression of mRNA for V1b in the hypothalamus or pituitary at any time point, but a small increase in the hippocampus after 2h only (22%, p<0.05) vs. time-matched saline controls.

This study supports data that AVP plays a key role in the release of ACTH after chronic stress, as no changes in mRNA in pituitary gland were seen post acute stressor. Thus, this novel data suggests that AVP plays an important role within the hippocampus following different acute inflammatory stressors administered locally or centrally. The up-regulation or down-regulation observed indicates a degree of plasticity within the hippocampus in response to different stressors. This should be substantiated with further investigations that could perhaps utilise the emerging antagonists for this receptor.

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2. T Shimazaki et al. Eur J Pharmacol. 2006 Aug 14; 543(1-3):63-7.
3. W Jing et al. Neurosci Lett. 2009 Feb 6; 450(3):306-10.