UC San Diego

Corticotropin-releasing factor (CRF), a 41 amino acid peptide, mediates endocrine, autonomic, and behavioral responses to stress. While 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 knockout (KO) mice suggest both anxiogenic and anxiolytic effects of CRF₂ receptor activation. This dissertation project examined 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 mouse lateral septum, a region with high CRF₂ receptor expression. Mice were tested in low or high stress (30 minutes of restraint) conditions, and behavior in the light-dark box, open field, and novel object test was assessed. In the low stress environment, the high dose of 500 ng of septal urocortin 2 increased anxiety-like behavior, but lower doses (1-100 ng) did not have consistent effects. However, in the high stress condition, 100 ng of septal urocortin 2 significantly increased anxiety-like behavior compared to vehicle. Urocortin 2 had no effect on anxiety-like behavior in CRF₂ receptor knockout mice and septal administration of the relatively selective CRF₂ receptor antagonist astressin-2B , but not the CRF₁ receptor selective antagonist antalarmin, blocked the anxiogenic effects of urocortin 2. Urocortin 2 infusion into the medial septum or lateral ventricle did not affect measures of anxiety-like behaviors. A lesion of the Edinger-Westphal nucleus, a source of urocortin 1 input to the lateral septum, decreased the anxiogenic effect of septal urocortin 2 during stress. These results indicate that the effect of septal CRF₂ receptor activation on anxiety-like behavior is dependent on the level of stress in the environment and may involve the release of urocortin 1 from the Edinger- Westphal nucleus. Under low stress conditions, activation of the CRF₂ receptor may have limited effect on anxiety- like behavior, but in a high stress environment, activation of both the CRF₁ receptor and the CRF₂ receptor will increase the anxiety response