The effect of lateral septum corticotropin-releasing factor receptor 2 activation on anxiety is modulated by stress

Corticotropin-releasing factor (CRF), a 41 amino acid peptide, mediates endocrine, autonomic, and behavioral responses to stress. Whereas the CRF1 receptor appears to contribute to anxiety associated with stress, the role of the CRF2 receptor remains unclear and may depend on drug dose, brain location, or testing environment. Results involving treatments with selective CRF2 receptor agonists or antagonists and the behavior of CRF2 receptor knock-out mice suggest both anxiogenic and anxiolytic effects of CRF2 receptor activation. The present study tested the hypothesis that the effect of CRF2 receptor activation on anxiety depends on the stress level of the animal. The selective CRF2 receptor agonist urocortin 2 was infused into the lateral septum of mice under low- or high-stress (30 min of immobilization) testing conditions, and then behavior in the light-dark box, open-field, and novel-object tests was assessed. In the low-stress environment, 240 pmol of septal urocortin 2 increased anxiety, but lower doses (0.48, 4.8, and 48 pmol) did not have consistent effects. However, in the high-stress condition, 48 pmol of septal urocortin 2 significantly increased anxiety compared with control in wild-type but not CRF2 receptor knock-out mice in the light-dark box. Septal administration of the relatively selective CRF2 antagonist astressin-2B, but not the CRF1-selective antagonist antalarmin, blocked the anxiogenic effects of urocortin 2. Urocortin 2 infusion into the medial septum or lateral ventricle did not affect anxiety measures. These results indicate that the effect of septal CRF2 receptor activation on anxiety is dependent on stress level.