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The Journal of Neuroscience, September 6, 2006, 26(36):9142-9152; doi:10.1523/JNEUROSCI.1494-06.2006

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Behavioral/Systems/Cognitive
The Effect of Lateral Septum Corticotropin-Releasing Factor Receptor 2 Activation on Anxiety Is Modulated by Stress

Brook Henry,^1,2,3 Wylie Vale,² and Athina Markou¹

¹Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, La Jolla, California 92037, ²Peptide Biology Laboratory, The Salk Institute, La Jolla, California 92037, and ³Department of Neurosciences, University of California, San Diego, La Jolla, California 92093

Correspondence should be addressed to Dr. Athina Markou, Department of Molecular and Integrative Neurosciences, SP30-2400, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Email: amarkou{at}scripps.edu

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.

Key words: CRF receptor 1; CRF receptor 2; urocortin 2; lateral septum; anxiety; stress

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Received March 28, 2005; revised June 13, 2006; accepted July 25, 2006.

Correspondence should be addressed to Dr. Athina Markou, Department of Molecular and Integrative Neurosciences, SP30-2400, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Email: amarkou{at}scripps.edu

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