This study used a multidimensional analysis of the behavioral responses to uCMS to examine the relevance of commonly used measures in this animal model of human depression. Etiological validity of the model is provided by the fact that stress is an important precipitating event both in the animal model and in clinical depression (Willner and Mitchell, 2002
). Thus, the use of uCMS to model depressive-like behavior is justified. In addition, construct validity is conferred to the model by the fact that the neurobiological processes triggered by stress are similar in animals and humans (Anisman and Matheson, 2005
; Steckler, 2001
). Nevertheless, the uCMS model of depression has remained poorly characterized in terms of the similarities with the symptom profile of clinical depression, namely in its anxiety and cognitive dimensions (Willner, 2005
). By demonstrating significant inter-domain behavioral interactions, the present work adds significantly to the face validity of the uCMS model of depression.
Our results confirm previous observations (Bekris et al., 2005
; D'Aquila et al., 1994
; Silva et al., 2008
; Willner et al., 1996
) that exposure to uCMS induces significant changes in mood-related behavior, characterized by an anhedonic state with decreased sucrose preference and increased immobility in the FST. Furthermore, the significant negative correlation observed between these two measures implies that the most anhedonic animals are the most helpless in the FST. This demonstration further strengthens the view that anhedonia and learned helplessness are core symptoms of depressive behavior.
The effect of uCMS in anxiety-related behavior has been a matter of recent debate (Kompagne et al., 2008
), with reports of decreased (D'Aquila et al., 1994
; Kopp et al., 1999
) and increased (Griebel et al., 2002a
; Maslova et al., 2002
) anxiety-like behavior in the EPM test after uCMS. In the present study, animals exposed to uCMS displayed marginally significant decreases in the percentage of time spent in the open arms of the EPM, suggesting the induction of a mildly anxious phenotype. To overcome this lack of reproducibility in the EPM, we evaluated the impact of uCMS in another paradigm of anxiety-related behavior – the NSF paradigm (Bodnoff et al., 1998
). Stress-induced anxiogenesis was confirmed in the NSF by the observation of a significant increase in the latency time to feeding. Since the results of the two tests of anxiety behavior (EPM and NSF) were not correlated, it would appear that each of these tests measures a distinct aspect of anxiety. In this respect, it should be noted that although both the EPM and NSF are conflict-based tests (Sousa et al., 2006
), performance in the EPM depends strongly on exploratory behavior, contrasting with behavior in the NSF which depends on appetitive drive because of the necessity of food deprivation. Accordingly, behavior in the EPM may be more sensitive to minor differences in environmental stimuli, possibly accounting for the disparate reports on the effects of uCMS.
Several studies have described uCMS-induced changes in cognitive function. For example, mice subjected to the uCMS paradigm show impairments in recognition memory (Elizalde et al., 2008
; Li et al., 2008
) as well as in spatial learning and memory (Song et al., 2006
). Our study failed to observe performance differences between stressed and control rats in a spatial learning task in the MWM. However, those animals exposed to uCMS displayed marked cognitive impairments when tested in a reverse learning task. Dissociation in cognitive performance in the different tasks may be suggestive of the greater vulnerability of the prefrontal cortex (a brain region implicated in reverse learning; Cerqueira et al., 2007a
) to the deleterious effects of uCMS, as compared to the hippocampus (which is primarily involved in spatial learning tasks). Supporting this interpretation, the analysis revealed poor correlation between performances on the two tasks.
A primary aim of this study was to assess the complex interactions between mood, anxiety and cognition. Previous studies reported correlations between immobility time in the FST and performance in an object recognition task (Elizalde et al., 2008
) and between sucrose preference and performance in a social avoidance test (Kompagne et al., 2008
). Analysis of data collected in the present study revealed a strong correlation between the two core symptoms of depressive behavior – anhedonia and learned helplessness – and both, the anxious phenotype (measured in the NSF) and cognitive impairments (reverse learning task). Furthermore, a significant correlation emerged between anxiety-related behavior in the NSF and cognitive performance in the reverse learning task. These results therefore show that the three different behavioral dimensions analyzed are likely to be interdependent, with each contributing to the dynamic processes that underlie depressive behavior.
The issue of whether the uCMS paradigm represents a valid model of depression was addressed by analyzing the ability of antidepressant drugs to ameliorate the various uCMS-induced changes in behavior (predictive validity). Consistent with previous work (Griebel et al., 2002a
; Song et al., 2006
), the present experiments demonstrated the efficacy of tricyclic agents (e.g. imipramine) and selective serotonin reuptake inhibitors (SSRI; e.g. fluoxetine) in reversing the anhedonic and helpless behaviors that develop after exposure to uCMS. Interestingly, imipramine showed a faster onset of action (with 1
week) as compared to fluoxetine whose first effects were observed only after 2
weeks; these different temporal profiles most likely reflect the dosages used, different mechanisms of drug action and/or neurochemical substrates.
The anxiolytic actions of antidepressant drugs have been extensively demonstrated in the NSF paradigm in stress-naive animals (Bodnoff et al., 1989
) as well as in transgenic models of depressive behavior, e.g. the serotonin transporter (SERT) knockout rat (Olivier et al., 2008
). In the present study, we found that both fluoxetine and imipramine displayed anxiolytic properties when uCMS-exposed rats were tested in the NSF, but not in the EPM. These findings reinforce the view that the EPM, although considered to be the gold standard in the development of novel anxiolytic agents (Dawson and Tricklebank, 1995
), may lack the desired sensitivity and reproducibility in stress exposure models and chronic antidepressant treatment.
Finally, our results clearly revealed that imipramine and fluoxetine attenuate uCMS-induced impairments in cognitive performance, as measured by the reverse learning task in the MWM. These findings concur with those of a previous study that reported partial reversal by the SSRI paroxetine of stress-induced impairment in an object recognition task (Elizalde et al., 2008
), as well as those of a recent clinical study that suggested the use of antidepressants for improving prefrontal cortex-dependent cognitive functions in patients with recurrent depression (Borkowska et al., 2007
In summary, the results of this study show that depression-like behavior, anxiety and impaired cognition as three highly inter-dependent variables that act in overlapping and synergistic modes; from a broader viewpoint, our results also show that there is a continuum between emotional changes and cognitive impairments. Further, these results demonstrate interactions between different behavioral domains that crosscut the disciplines of psychiatry and neurology.