title: DPP4-deficient congenic rats display blunted stress, improved fear extinction and increased central NPY.
abstract: BACKGROUND
  Inhibitors of dipeptidyl peptidase 4 (DPP4, CD26) are used for the treatment of type 2 diabetic patients and better glucose tolerance has been confirmed in functionally DPP4-deficient congenic rats (DPP4mut), along with immunological alterations and, interestingly, a stress-resilient phenotype. All these findings are in agreement with the "moonlighting" properties of DPP4, whose proteolytic action is responsible for the inactivation of a number of regulatory peptides including, but not limited to, neuropeptide Y (NPY). Among all candidate substrates, DPP4 displays highest affinity for NPY, an endogenous anxiolytic neurotransmitter that is suggested as a candidate biomarker in post-traumatic stress disorder (PTSD) and depression.
  
  
  RESULTS
  Central and peripheral NPY levels were measured by ELISA in DPP4mut and DAwt rats revealing a significantly higher concentration of the peptide in the CSF of DPP4mut animals. This finding positively correlated with the blunted stress phenotype measured on an analgesia-meter. Additionally, when a classical fear-conditioning paradigm was investigated, short-term fear extinction was significantly potentiated in DPP4mut rats as compared to wt controls.
  
  
  CONCLUSIONS
  Our findings indicate a positive correlation between reduced stress-responsiveness and increased central NPY, in DPP4mut rats. Most interestingly, the behavioral phenotype extends to facilitation of fear extinction. These observations raise further interest in DPP4-modulating drugs for the potential effect on NPY metabolism, as a therapeutic tool for psychiatric conditions such as anxiety disorders and PTSD.
authors: Department of Experimental Therapy, Präklinisches Experimentelles Tierzentrum, Univerisitätsklinikum Erlangen, 91054 Erlangen, Germany. Electronic address: Fabio.Canneva@uk-erlangen.de.
authors: Fabio
authors: F
authors: Canneva
authors: Department of Child and Adolescent Mental Health, University Clinic of Erlangen, 91054 Erlangen, Germany.
authors: Yulia
authors: Y
authors: Golub
authors: Department of Experimental Therapy, Präklinisches Experimentelles Tierzentrum, Univerisitätsklinikum Erlangen, 91054 Erlangen, Germany.
authors: Joerg
authors: J
authors: Distler
authors: Department of Experimental Therapy, Präklinisches Experimentelles Tierzentrum, Univerisitätsklinikum Erlangen, 91054 Erlangen, Germany.
authors: Julia
authors: J
authors: Dobner
authors: Department of Experimental Therapy, Präklinisches Experimentelles Tierzentrum, Univerisitätsklinikum Erlangen, 91054 Erlangen, Germany.
authors: Sandra
authors: S
authors: Meyer
authors: Department of Experimental Therapy, Präklinisches Experimentelles Tierzentrum, Univerisitätsklinikum Erlangen, 91054 Erlangen, Germany.
authors: Stephan
authors: S
authors: von Hörsten
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D001921:Brain / Q000378:metabolism*; D003214:Conditioning, Classical; D018819:Dipeptidyl Peptidase 4 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005108:Extinction, Psychological; D005239:Fear; D009154:Mutation; D009478:Neuropeptide Y / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*
chemical_list: D009478:Neuropeptide Y; D012333:RNA, Messenger; D017476:Receptors, Neuropeptide Y; C000602659:DPP4 protein, rat; D018819:Dipeptidyl Peptidase 4
keywords: Anxiety; CD26; DPP4; Fear; NPY; Stress