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

Abstract

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.