The forced swim test (FST) is a behavioral paradigm that is widely used as a screening test for antidepressant activity in rodents. The objectives of the present study were to characterize the corticosterone and immune responses and in addition to examine neurotransmitter levels, in five brain regions at intervals (15, 30, 60, 90, and 120 min) following the second exposure to the FST. There was a significant but transient reduction in noradrenaline and 5-HT concentrations, in the hypothalamus 15 min post-FST exposure. 5-HT turnover in the frontal cortex and amygdala was significantly increased between 20-120 min post-FST exposure. The FST elicited a robust corticosterone response that peaked significantly at 30 min and had almost returned to baseline 120 min after exposure. There was a significant reduction in total white blood cell count 120 min after the FST, which was accompanied by a sig nificantly reduced percentage of lymphocytes 90 and 120 min post-FST exposure. In addition, there was a significant but transient suppression of both PHA and Con A-induced lymphocyte proliferation 15 min following FST exposure. This study demonstrates that there are neurochemical changes that are coincident with the endocrine and immune changes associated with FST exposure in rats. Furthermore, this model could be used to examine the effects of manipulation of this stress response by antidepressant drugs. Such an investigation could add to our understanding of the interactions between antidepressants,stress and the neuroendocrine and immune systems. (C) 1997 Elsevier Science Inc.