when compared to the concentrations in the unstressed control animals. This suggests an

enduring change in the circadian regulation of the HPA axis following chronic social

defeat. Overall, the effects of six days of social defeat stress exceeded the results attained

with the fifteen days of CVS previously described.

 The brain sites activated by social defeat have been studied using c-fos

immunohi stochemi stry. The immediate-early gene (IEG) c-fos is expressed in many cells

in the brain, but typically at very low basal levels. C-fos and other IEGs are intracellular

signaling mechanisms that regulate gene transcription and expression of various

neuropeptides and trophic molecules in response to stress (for review, see Sabban and

Kvetnansky, 2001). Various stressful stimuli can initiate increased levels of c-fos mRNA

expression, lasting for minutes to hours. For instance, social defeat produces elevated

c-fos expression in limbic, limbic-associated, and brainstem sites in both hamsters and

rats one hour after a single defeat session (Kollack-Walker et al., 1997; Martinez et al.,

1998). These results point to the brain structures that are important in the processing of

emotionally stressful events. However, after repeated social defeat sessions in rats, the

pattern of neuronal activity was modified, despite the fact that intruder submissive

behavior persisted across trials. C-fos mRNA expression endured for many of these

limbic and brainstem nuclei, while other limbic and brainstem regions exhibited a

decrease in the social defeat-induced c-fos mRNA expression.

 The Porsolt swim test, originally described by Porsolt and colleagues (1978), is the

most commonly utilized behavioral test for screening antidepressant treatments in rats

and has been used to evaluate the behavioral effects of stress exposure. Immobility

during the inescapable swim is measured as an indicator of behavioral despair or