title: Antidepressant-like effects of kappa-opioid receptor antagonists in Wistar Kyoto rats.
abstract: The Wistar Kyoto (WKY) rat strain is a putative genetic model of comorbid depression and anxiety. Previous research showing increased kappa-opioid receptor (KOR) gene expression in the brains of WKY rats, combined with studies implicating the KOR in animal models of depression and anxiety, suggests that alterations in the KOR system could have a role in the WKY behavioral phenotype. Here, the effects of KOR antagonists in the forced swim test (FST) were compared with the WKY and the Sprague-Dawley (SD) rat strains. As previously reported, WKY rats showed more immobility behavior than SD rats. The KOR antagonists selectively produced antidepressant-like effects in the WKY rats. By contrast, the antidepressant desipramine reduced immobility in both strains. Brain regions potentially underlying the strain-specific effects of KOR antagonists in the FST were identified using c-fos expression as a marker of neuronal activity. The KOR antagonist nor-binaltorphimine produced differential effects on the number of c-fos-positive profiles in the piriform cortex and nucleus accumbens shell between SD and WKY rats. The piriform cortex and nucleus accumbens also contained higher levels of KOR protein and dynorphin A peptide, respectively, in the WKY strain. In addition, local administration of nor-binaltorphimine directly into the piriform cortex produced antidepressant-like effects in WKY rats further implicating this region in the antidepressant-like response to KOR antagonists. These results support the use of the WKY rat as a model of affective disorders potentially involving KOR overactivity and provide more evidence that KOR antagonists could potentially be used as novel antidepressants.
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Carr
authors.forename: Debra A
authors.initials: DA
authors.lastname: Bangasser
authors.forename: Thelma
authors.initials: T
authors.lastname: Bethea
authors.forename: Matthew
authors.initials: M
authors.lastname: Young
authors.forename: Rita J
authors.initials: RJ
authors.lastname: Valentino
authors.forename: Irwin
authors.initials: I
authors.lastname: Lucki
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003866:Depressive Disorder / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D009833:Olfactory Pathways / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013045:Species Specificity
chemical_list: D000928:Antidepressive Agents; D017473:Receptors, Opioid, kappa