Background and aims

Deletion of neuropeptide Y (NPY) Y2 and Y4 receptors reduces anxiety-like and depression-related behaviour [1]. We have previously found that Y2 receptor knockout (Y2-/-) mice are particularly sensitive to the short-term anxiogenic effect of immune stress evoked by systemic lipopolysaccharide (LPS) [2]. In the present study we investigated whether LPS challenge has long-term effects on anxiety-like and depression-related behaviour and whether these effects are altered in Y2-/- and Y4-/- mice.

Materials and methods

Adult control and germline Y2-/- and Y4-/- mice were used. Anxiety-like behaviour was assessed on the elevated plus maze, and depression-related behaviour was estimated with the forced swim test. These tests were carried out 1 day or 4 weeks after a single intraperitoneal injection of LPS (0.83 mg/kg) or vehicle (sterile saline).

Results

Relative to control animals, vehicle-treated Y2-/- and Y4-/- mice were less anxious and displayed reduced depression-like behaviour. One day after LPS injection, anxiety-like behaviour remained unaltered in control animals but was markedly enhanced in Y2-/- and Y4-/- mice. Four weeks post-treatment, the anxiogenic effect of LPS was still seen in Y4-/- mice but had gone in control and Y2-/- mice. Depression-related behaviour was enhanced 1 day after LPS treatment in control and Y2-/- mice, but not in Y4-/- mice. Four weeks post-treatment, the effect of LPS challenge to increase depression-like behaviour had waned in control mice, but was still present in Y2-/- mice and was first observed in Y4-/- mice.

Conclusion

Y2-/- and Y4-/- mice are particularly susceptible to the effects of immune stress to cause a long-term enhancement of anxiety- and depression-like behaviour. With Y2 and Y4 receptors playing distinct roles in these persistent alterations of emotional-affective behaviour, it is emerging that endogenous NPY has an important bearing on immune signalling to the brain.