Preproenkephalin knockout mice show no depression-related phenotype.
Clinical, preclinical, and pharmacological studies have suggested that decreased enkephalin tone is associated with depression-like symptoms and increase in enkephalin signaling could have a therapeutic value in the treatment of depression. In this study we demonstrate that, surprisingly, animals lacking enkephalin (preproenkephalin, Penk1(-/-)) showed no depression-related phenotype in the Porsolt forced swimming or tail suspension tests. Moreover, Penk1(-/-) mice had a lower frequency of depression-related behavior in stress-induced hypoactivity and ultrasonic vocalization models of depression, similar to animals treated with antidepressant drugs, although this effect was specific to the genetic background. In addition, there was no significant difference in the efficacy of antidepressant reference compounds in wild-type and knockout animals. Nialamide and amitriptyline were even slightly more effective in animals with genetic deletion of Penk1, whereas the minimal effective dose of imipramine and fluoxetine was the same in the two genotypes. The dual peptidase inhibitor RB-101 was also effective in Penk1(-/-) as well as in Penk1(-/-)/Pdyn(-/-) animals, although its efficacy was somewhat reduced compared with wild-type animals. This result was also surprising because the antidepressant effects of RB-101 were thought to be due to the elevation of enkephalin levels.
Bilkei-Gorzo
Andras
A
Department of Molecular Psychiatry, University of Bonn, Bonn, Germany. abilkei@uni-bonn.de
Michel
Kerstin
K
Noble
Florence
F
Roques
Bernard P
BP
Zimmer
Andreas
A
D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003863:Depression / Q000188:drug therapy / Q000235:genetics*; D004195:Disease Models, Animal; D004220:Disulfides / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004745:Enkephalins / Q000172:deficiency*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D019417:Hindlimb Suspension / Q000502:physiology; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout / Q000502:physiology*; D009043:Motor Activity / Q000502:physiology; D009526:Nialamide / Q000627:therapeutic use; D010641:Phenotype; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D011498:Protein Precursors / Q000172:deficiency*; D013550:Swimming; D014828:Vocalization, Animal / Q000502:physiology
D000928:Antidepressive Agents; D004220:Disulfides; D004745:Enkephalins; D004791:Enzyme Inhibitors; D011498:Protein Precursors; C074024:RB 101; D010649:Phenylalanine; C033660:preproenkephalin; D009526:Nialamide