Selectively bred Wistar–Kyoto rats: an animal model of depression and hyper-responsiveness to antidepressants

The Wistar–Kyoto (WKY) rat strain demonstrates endogenous hormonal and behavioral abnormalities that emulate many of those found in symptom-presenting depressive patients. Evidence suggests that the WKY strain may harbor heterogeneity not found in other inbred strains, including greater behavioral and genetic variability. We took advantage of this variability and selectively bred WKY for ‘depressive’ behavior using immobility in the forced swim test (FST) as a functional selector. Successive generations of selective breeding resulted in rats that exhibited the extremes of immobility in the FST: ‘WKY most immobile’ (WMI) and ‘WKY least immobile’ (WLI). Male WMI rats also showed significantly decreased activity in the open field test (OFT). Plasma corticosterone (CORT) response to restraint stress was significantly lower and less variable in WMI compared to WLI males. Subacute treatment of males with several classes of antidepressant had different effects on FST behavior in the two substrains. Both desipramine (10 mg/kg body weight), a tricyclic antidepressant, and phenelzine (7.5 mg/kg), a monoamine oxidase inhibitor, significantly and drastically decreased FST immobility in WMI. In contrast, WLI showed a limited response to these antidepressants. Neither substrain responded to fluoxetine (10 mg/kg), a selective serotonin reuptake inhibitor. These data show that selective breeding of WKY rats has resulted in two substrains with reduced variability and differing responsiveness to antidepressants, which represent a novel means to dissect the molecular mechanisms underlying depressive behavior.