Stressor during Early Adolescence in Hyperreactive Female Wistar Kyoto Rats Induces a 'Double Hit' Manifested by Variation in Neurobehaviors and Brain Monoamines.

Stress is an additive factor in the development of depressive-like profiles that mainly onsets during adolescence. However, effects of early post-weaning stress on developing brain neurochemical pathways in inducing anxiety- and depressive-like profiles in vulnerable females have not been extensively studied. The Wistar Kyoto (WKY) rat, a putative model of adolescent depression and stress-sensitivity could elucidate the pathophysiology of stress-related depression in vulnerability. Through such an approach, links between inherent risk for predisposition to depression and homotypic stress, as in a 'double hit' would unravel endocrine regulation, interference in developing neural pathways and neurobehaviors. Here, early adolescent WKY female rats were subjected to 1-h physical restraint over 7 days followed by neurobehavioral testing in the elevated plus maze (EPM) and forced swim test (FST). The stressor's effectiveness was assayed by plasma corticosterone (CORT) and altered functioning in depression-implicated brain areas by assaying monoamines/metabolites. Homotypic stress induced an anxiolytic-like response in the EPM with learned helplessness and reduced struggling behavior in FST. Significant elevation in CORT levels (p < 0.05) indicated an upregulated HPA axis. Medial prefrontal cortex, a still maturing brain area, exhibited increased serotonin (5-HT) metabolite (p < 0.01) and turnover rates (p < 0.01) indicative of altered/maladaptive serotonergic functioning. Nucleus accumbens (p < 0.05) and dorsal striatum (p < 0.01) also depicted increased 5-HT metabolite, with the latter also demonstrating reduced Dopamine turnover (p < 0.01) as a result of homotypic stress. Hence, female WKY rats could constitute a diathesis-stress model to study underlying mechanisms of stress-related depression.

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

BACKGROUND: Depression often manifests during adolescence when the development and networking of social and emotional brain areas is being influenced by hormones. The Wistar Kyoto (WKY) rat has been proposed as an animal model of adolescent depression with various face, construct, and predictive validities for clinical depression having been established. PURPOSE: The influence of the estrous cycle on anxiety- and depression-like behaviors in female adolescents may be tested out further using this model. METHODS: Female adolescent WKY rats were tested for anxiety- and depression-like behaviors in the elevated plus maze and forced swim test (FST) during different phases of the estrous cycle with inbred, age-, and phase-matched Wistar rats as controls. RESULTS: Wistars in proestrus-estrus demonstrated reduced anxiety levels. WKY also demonstrated increased open arm time and entries and closed arm time, but less than Wistars, and as closed arm entries remained unaffected, it did not translate into a lowering of the anxiety levels. Risk taking and risk assessment behaviors were not affected by estrous phases in WKY, though exploratory behavior was reduced in proestrus-estrus. In Wistars, increased risk taking and decreased risk assessment behaviors were observed during proestrus-estrus. Increased immobility in the FST, indicative of learned helplessness was not influenced by phase in the WKY, which was at variance with Wistars that demonstrated phase-specific differences. CONCLUSION: Results indicate a masking effect of indicative hormones in this putative model of adolescent depression, with implications for an unravelling of the steroid milieu in predisposed adolescent depression and for taking phase-specific time windows into account for therapeutic interventions.

Anxiety- and depressive-like profiles during early- and mid-adolescence in the female Wistar Kyoto rat.

Approaches for the development of preclinical models of depression extensively use adult and male animals owing to the discrepancies arising out of the hormonal flux in adult females and adolescents during attainment of puberty. Thus the increased vulnerability of females towards clinical depression and anxiety-related disorders remains incompletely understood. Development of clinical models of depression in adolescent females is essential in order to evolve effective treatment strategies for adolescent depression. In the present study, we have examined the anxiety and depressive-like profiles in a putative animal model of childhood depression, the Wistar Kyoto (WKY) rat, during early adolescence (∼postnatal day 30) and mid-adolescence (∼postnatal day 40). Female adolescent WKY rats, tested on a series of behavioural tests modelling anxiety- and depressive-like behaviours with age-matched Wistars as controls, demonstrated marked differences during early adolescence in a strain- and age-specific manner. Anxiety indices were obtained from exposure to the elevated plus maze, where social communication vide 50-kHz ultrasonic vocalizations was also assessed, while immobility and other parameters in the forced swim test were screened for depressive-like profiles. Sucrose preference, used as a measure of anhedonia in animals, was lower in WKYs at both ages tested and decreased with age. Anxiety-related behaviours were prominent in WKY rats only during early adolescence. WKY female rats are anxious during early adolescence and exhibit anhedonia as a core symptom of depression during early- and mid-adolescence, thus indicating that inclusion of female animals in preclinical trials is essential and will contribute to gender-based approaches to diagnosis and treatment of adolescent depression in females.