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Cortagine, a Specific Agonist of Corticotropin-Releasing Factor Receptor Subtype 1, Is Anxiogenic and Antidepressive in the Mouse Model
Hossein Tezval, Olaf Jahn, Cedomir Todorovic, Astrid Sasse, Klaus Eckart, Joachim Spiess and Michael G. Rosenfeld
Proceedings of the National Academy of Sciences of the United States of America
Vol. 101, No. 25 (Jun. 22, 2004), pp. 9468-9473
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3372674
Page Count: 6
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Two subtypes of the corticotropin-releasing factor (CRF) receptor, CRF1 and CRF2, differentially modulate brain functions such as anxiety and memory. To facilitate the analysis of their differential involvement, we developed a CRF1-specific peptidic agonist by synthesis of chimeric peptides derived from human/rat CRF, ovine CRF (oCRF), and sauvagine (Svg). High affinity to the CRF-binding protein was prevented by introduction of glutamic acid in the binding site of the ligand. The resulting chimeric peptide, [ Glu21, Ala40][ Svg1-12]× [human/rat CRF14-30]× [ Svg30-40], named cortagine, was analyzed pharmacologically in cell culture by using human embryonic kidney-293 cells transfected with cDNA coding for CRF1 or CRF2, in autoradiographic experiments, and in behavior experiments using male C57BL/6J mice for its modulatory action on anxiety- and depression-like behaviors with the elevated plusmaze test and the forced swim test (FST), respectively. We observed that cortagine was more selective than oCRF, frequently used as CRF1-specific agonist, in stimulating the transfected cells to release cAMP. Cortagine's specificity was demonstrated in autoradiographic experiments by its selective binding to CRF1 of brain sections of the mouse. After injection into the brain ventricles, it enhanced anxiety-like behavior on the elevated plus-maze at a lower dose than oCRF. Whereas at high doses, oCRF injected into the lateral intermediate septum containing predominantly CRF2 increased anxiety-like behavior as CRF2-specific agonists do, cortagine did not. In contrast to its anxiogenic actions, cortagine reduced significantly the immobility time in the FST as described for antidepressive drugs. Thus, cortagine combines anxiogenic properties with antidepressive effects in the FST.
Proceedings of the National Academy of Sciences of the United States of America © 2004 National Academy of Sciences