A cognitive deficit induced in rats by chronic intermittent cold stress is reversed by chronic antidepressant treatment

Abstract

We have previously reported that 14-d chronic intermittent cold (CIC) stress induced a cognitive deficit in reversal learning on the rat attentional set-shifting test. This effect may be related to dysregulation of 5-HT function in orbitofrontal cortex, as a model of cognitive dysfunction in depression. To test the ability of chronic antidepressant drug treatment to reverse the cognitive deficit induced by CIC, it was first necessary to assess the temporal characteristics of the CIC-induced cognitive deficit. Thus, in the first experiment, we assessed the duration of the cognitive deficit following 2-wk CIC stress. Replicating previous experiments, CIC induced a reversal learning deficit tested 3 d after the last cold exposure. However, cognitive performance of CIC-stressed rats was no different from unstressed controls when tested 7, 14 or 21 d after termination of the stress treatment. We next compared behaviour 3 d after 2-wk CIC to that seen 3 d after 5-wk CIC, and found similar deficits in reversal learning. Thus, in the final experiment, antidepressant drug treatment was initiated after 2-wk CIC stress, and was maintained for 3 wk, concurrent with the continuation of CIC stress. Both chronic and acute treatment with the selective serotonin reuptake inhibitor, citalopram, but not the norepinephrine reuptake blocker, desipramine, reversed the cognitive deficit induced by CIC stress. Thus, this stress-induced cognitive deficit may be a useful model for cognitive deficits related to prefrontal cortical hypoactivity in depression, and for investigating neurobiological mechanisms underlying the beneficial effects of chronic antidepressant drug treatment.

Figure 1

Cognitive effects of 14-day CIC stress, tested at 3, 7, 14 and 21 days after termination of cold stress exposure. CIC induced a reversal learning deficit tested 3 days after the last stress exposure (A). However, this effect dissipated at 7, 14, and 21 days after cold exposure (B–D). At day 3, CIC–stressed rats required significantly more trials to reach criterion on the R1 reversal task compared to non-stressed controls (*p < 0.01 compared to unstressed control rats on the same task; mean ± SEM; n = 8–12 per group).

Figure 2

Exposure to CIC stress for either 2- or 5-weeks induced a selective and significant impairment in reversal learning compared to unstressed controls, tested 3 days after the termination of chronic cold stress exposure (*p < 0.01 compared to unstressed control rats on the same task; +p < 0.05 two-week compared to 5-week CIC stressed rats on the same task; mean ± SEM; n= 7–8 per group).

Figure 3

There were no anxiety-like changes in open-arm exploratory behavior on the elevated plus-maze after CIC stress exposure for 2- or 5-weeks, measured either as OTR for Time (panel A) or OTR for Entries (panel B; mean ± SEM; n= 7–8 per group).

Figure 4

Effects of chronic antidepressant drug treatment, initiated after 2-weeks of CIC stress and maintained during continuation of CIC stress exposure for 3 more weeks. Panel A: Chronic treatment with CIT (20 mg/kg/day) reversed the CIC stress-induced cognitive deficit (*p < 0.001 compared to non-stressed control rats on the same task; +p < 0.001 compared to vehicle-treated CIC-stressed rats on the same task; mean ± SEM; n = 7–9 per group). Panel B: Chronic treatment with DMI (7.5 mg/kg/day) had no beneficial effect on the elevated number of trials to criterion on the R1 task after CIC stress, comparable to vehicle-treated CIC-stressed rats. In this experiment (but not in any others), CIC stress also increased trials to criterion on the ED cognitive set-shifting task, and DMI also did not reverse this effect. *p < 0.001 compared to vehicle-treated, non-stressed control rats on the same task; ^$ p < 0.05 compared to vehicle-treated, non-stressed control rats on the same task; mean ± SEM; n = 7–8 per group).

Figure 5

Effects of acute antidepressant drug treatment, given 30 min prior to the R1 reversal task. Panel A: Acute treatment with CIT (5 mg/kg, i.p.) improved performance of CIC stress-stressed rats on the R1 reversal task (*p < 0.01 compared to non-stressed control rats on the same task; +p < 0.01 compared to vehicle-treated CIC-stressed rats on the same task; mean ± SEM; n = 8 per group). Panel B: Acute treatment with DMI (5 mg/kg, i.p.) had no beneficial effect on the increased number of trials required to reach criterion on the R1 task after CIC stress, comparable to vehicle-treated CIC-stressed rats. (*p < 0.05 compared to vehicle-treated, non-stressed control rats; mean ± SEM; n = 6 per group).