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

Abstract

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. Molecular Psychiatry (2003) WKY rats are hyper-reactive to stress and show dysregulation of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes. We previously showed that compared to Wi rats, basal plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels of WKY rats remain significantly higher for several hours after the diurnal peak. 2 They also display increased steadystate levels of anterior pituitary pro-opiomelanocortin (POMC) mRNA and exaggerated plasma ACTH responses to acute and chronic stress compared to other rat strains. 3,4 A number of laboratories have found that WKY rats exhibit depressive-like behavior in a wide range of accepted behavioral paradigms. Increased immobility in the forced swim test (FST), considered as a measure of depressive-like behavior, 5-7 has been found in many studies. [8][9][10][11][12] Among other assessments of depressive or anxious behavior, WKY rats also show decreased activity in the open field test (OFT), a measure of anxiety/fear, 9,13 and in the defensive burying test (DB), a potential measure of passive coping. 9 Several studies have found that WKY rats show reduced responsiveness to tricyclic antidepressants (TCA) compared to Brown Norway, Lewis, Fisher 344 (F344), 11 and Sprague Dawley (SD) 14 rats, while others have reported increased responsiveness to TCA antidepressants. 15 Fluoxetine (selective serotonin reuptake inhibito...

Estrous Cycle Phase-Dependent Changes in Anxiety- and Depression-Like Profiles in the Late Adolescent Wistar-Kyoto Rat

“…More studies exist of it being used as a control for the spontaneously hypertensive rat. But they also harbor heterogeneity not found in other inbred strains, including greater behavioral and genetic variability [8] .…”

“…When compared to the Wistar strain, adrenocorticotropic hormone and corticosterone levels are increased [6] . They also exhibit neurochemical abnormalities in several systems (dopaminergic and noradrenergic), with reduced levels of monoamines, as indicated in depression, as well as in peripheral hormones such as the thyroid stimulating hormone [7,8] .…”

“…Thus, the WKY is said to be a good model for endogenous depressive behavior [8,9] . Their impaired adaptive capability makes them more susceptible to depressive behaviors.…”

Animal Models of Anxiety Vulnerability - The Wistar Kyoto Rat

“…Much of the past research has focused on altering behaviors in the FST. Drugs which act by blocking NE transporters reduced immobility in FST and increase activity in the OFT in WKY rats Lucki and Nobler, 1985;Pare, 1992b;Pare et al, 2001;Will et al, 2003). Thus, increasing NE availability affects inhibited temperament of WKY rats.…”

Convergent functional genomics of psychiatric disorders

“…That work was subsequently extended to look at the gene expression changes in blood from the animals on the different treatments, as a way of identifying brain-blood biomarkers [Le-Niculescu et al, 2009b]. Niculescu et al, 2008Niculescu et al, , 2011b Nile grass rat [Ashkenazy-Frolinger et al, 2010] Methamphetamine [Niculescu et al, 2000;Macedo et al, 2013] Learned helplessness [Mingmalairak et al, 2010] CLOCK [Roybal et al, 2007;Mukherjee et al, 2010;Arey et al, 2013] Flinders Sensitive Line (FSL) rats [Malkesman and Weller, 2009] Methamphetamine/valproate [Ogden et al, 2004] Isolation housing [Le-Niculescu et al, 2008;Niwa et al, 2013] CTNNB1 [Gould et al, 2008] Wistar Kyoto (WKY) rats [Will et al, 2003;Malkesman and Weller, 2009] Amphetamine-chlordiazepoxide [Kelly et al, 2009] Forced swim test [Le-Niculescu et al, 2008] POLG [Kasahara et al, 2006;Kubota et al, 2010] Madison (MSN) [Saul et al, 2012] Lithium [Gould et al, 2007;Johnson et al, 2009;Kovacsics and Gould, 2010] Tail suspension test [Le-Niculescu et al, 2008] HINT1 [Barbier and Wang, 2009] Other mood stabilizers: Lamotrigene [Li et al, 2010], Topiramate [Bourin et al, 2009] Restraint stress [Johnson et al, 2009;Koo et al, 2010] GRIN2A [Taniguchi et al, 2009] Ouabain [Herman et al, 2007] Shock-induced aggression …”