BEHAVIOURAL AND PHARMACOLOGICAL VALIDATION OF CHRONIC SOCIAL STRESS AS A MODEL OF DEPRESSIVE-LIKE SYMPTOMS IN RATS

Abstract

In order to develop a model of chronic social stress in rats, in the first study the male Wistar rats were subjected to five weeks daily exposure to social defeat. This protocol resulted in a variety of behavioural changes in the rodents that might be regarded as behavioural correlates of depressive-like symptoms in humans. They are: 1) the prolonged immobility time in the forced swimming test symptomatic of decreased motivation and behavioural despair; 2) the reduced preference for sweet sucrose solution, a putative indicator of anhedonia in rodents; and 3) the reduced locomotor and exploratory activity suggesting changes in incentive motivation and emotionality. Furthermore, these effects were associated with decreased body weight gain and increased weight of adrenal glands, both organic correlates of stress effects.Based on the obvious face validity and to investigate whether this model also has predictive validity the question has been addressed how well stressed rats respond favourably to the different classes of antidepressant drugs such as Selective Serotonin Reuptake Inhibitors (Citalopram 30 mg/kg/day and Fluoxetine 10 mg/kg/day) or Selective Noradrenaline Reuptake Inhibitors (Reboxetine 40 mg/kg/day). To mimic a realistic situation of antidepressant intervention, the animals started to be treated after stress-induced alterations had been established such as reduction in locomotor and exploratory activity. Four weeks of daily treatment with all the tested antidepressants reversed the majority of adverse effects of chronic social stress at least on behavioural level. The drugs showed different profiles of action what is in agreement with a clinical data. Importantly, antidepressant drugs did not influence the behaviour of control animals. This is in agreement with the effects of antidepressant drugs in healthy human and animal subjects. The drug monitoring performed at the end of experiments allowed to determine plasma levels of each drug and their metabolites at which the particular behavioural and physiological effects were observed. After four weeks of oral treatment the plasma concentrations of the drugs were similar to those reported in human patients treated with therapeutically effective doses.In the last part of the study that was designed to evaluate the specificity of antidepressant treatment, the animals were treated with neuroleptic drug Haloperidol and anxiolytic Diazepam. In order to mimic clinical situation, Haloperidol (2 mg/kg/day) was administered chronically while Diazepam (1 mg/kg i.p.) was applied acutely. The treatment with Haloperidol resulted in reduced locomotor and exploratory activity, decreased preference to sucrose solution and prolonged immobility time in forced swim test. The treatment worsened the adverse effects of chronic social stress having effects similar to stress on reward and motivation related behaviours. Treatment with Diazepam caused reduction of anxiety related behaviours as measured in elevated plus maze in control animals. However had no beneficial effects on socially stressed individuals. Neither sucrose preference nor performance in forced swim test was affected by Diazepam treatment. These results provided the proof for specificity of antidepressant treatment in reversing socially induced correlates of depressive symptoms in rats.