Development and use of "stress" animal models of depression to study the mode of action of antidepressant drug treatments

Bate, Elizabeth (2003). Development and use of "stress" animal models of depression to study the mode of action of antidepressant drug treatments. PhD thesis The Open University.



The effect of the exposure of male BALB/c mice to sensory stimuli from male Brown Norway rats was assessed using plasma corticosterone (CORT) concentrations and glucocorticoid receptor (GR) binding in the cortex, and a number of behavioural measures (sucrose preference, food intake and elevated plus-maze tests). Following 8 weeks of exposure, stressed mice showed a 97% increase in plasma CORT concentrations but GR binding, sucrose preference, food intake, and the elevated plus maze (EPM) measurements were unaltered. In conclusion, this study suggests that chronic exposure of mice to sensory stimuli from rats increases stress hormones and may provide a natural predator model of stress. The effects of acute and chronic restraint stress with the administration of paroxetine (10 mg/kg p. o.), a selective serotonin reuptake inhibitor (SSRI), on the hypothalamic-pituitary-adrenocortical (HPA) axis were studied in adult male Wistar rats. Three weeks of restraint stress induced a 700% increase in plasma CORT and a 100% increase in adrenocorticotrophin (ACTH) concentration, whilst decreasing GR binding in the cortex by 34% and hippocampus by 30%, and a 24% decrease in food intake. Administration of paroxetine induced a 166% increase in plasma CORT concentration, whilst decreasing GR mRNA levels by 45% in the cortex and food intake by 25%. Paroxetine administration decreased the stress-induced plasma CORT by 80% but enhanced ACTH concentration by 78%, partially reversing the stress-induced downregulation of GR in the cortex by 34%, increasing GR mRNA in the cortex by 58%, reducing BDNF mRNA in the cortex by 30%, and reversed the stress-induced decrease in food intake by 22%. Taken together, these results suggest that restraint stress provoked a stress response, which remained elevated after three weeks, and feedback inhibition on the HPA axis following stress was facilitated by treatment with paroxetine.

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