Cortagine, a specific agonist of corticotropin-releasing factor receptor subtype 1, is anxiogenic and antidepressive in the mouse model.
Two subtypes of the corticotropin-releasing factor (CRF) receptor, CRF(1) and CRF(2), differentially modulate brain functions such as anxiety and memory. To facilitate the analysis of their differential involvement, we developed a CRF(1)-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, [Glu(21),Ala(40)][Svg(1-12)]x[human/rat CRF(14-30)]x[Svg(30-40)], named cortagine, was analyzed pharmacologically in cell culture by using human embryonic kidney-293 cells transfected with cDNA coding for CRF(1) or CRF(2), 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 plus-maze test and the forced swim test (FST), respectively. We observed that cortagine was more selective than oCRF, frequently used as CRF(1)-specific agonist, in stimulating the transfected cells to release cAMP. Cortagine's specificity was demonstrated in autoradiographic experiments by its selective binding to CRF(1) 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 CRF(2) increased anxiety-like behavior as CRF(2)-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.
Tezval
Hossein
H
Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, Hermann Rein Strasse 3, D-37075 Goettingen, Germany.
Jahn
Olaf
O
Todorovic
Cedomir
C
Sasse
Astrid
A
Eckart
Klaus
K
Spiess
Joachim
J
D000595:Amino Acid Sequence; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D003346:Corticotropin-Releasing Hormone; D006801:Humans; D007700:Kinetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013550:Swimming; D014162:Transfection; D000099052:CRF Receptor, Type 1
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; C101531:CRF receptor type 2; D018019:Receptors, Corticotropin-Releasing Hormone; D011993:Recombinant Fusion Proteins; C488590:cortagine; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone