Chronic intermittent cold stress and serotonin depletion induce deficits of reversal learning in an attentional set-shifting test in rats - PubMed (original) (raw)

Chronic intermittent cold stress and serotonin depletion induce deficits of reversal learning in an attentional set-shifting test in rats

M Danet S Lapiz-Bluhm et al. Psychopharmacology (Berl). 2009 Jan.

Abstract

Rationale: Chronic stress perturbs modulatory brain neurotransmitter systems, including serotonin (5-HT), and is a risk factor for psychiatric disorders such as depression. Deficits in cognitive flexibility, reflecting prefrontal cortical dysfunction, are prominent in such disorders. Orbitofrontal cortex (OFC) has been implicated specifically in reversal learning, a form of cognitive flexibility modulated by 5-HT.

Objectives: The objectives of the study were (1) to assess the effects of chronic intermittent cold (CIC) stress, a potent metabolic stressor, on performance of rats in an attentional set-shifting test (AST), and (2) to assess a possible role for serotonin in CIC-induced deficits and test the effects of acute serotonin reuptake blockade.

Materials and methods: Male Sprague-Dawley rats were exposed to CIC stress (14 days x 6 h/day at 4 degrees C) before testing on the AST. In subsequent experiments, brain 5-HT was depleted in naïve rats with para-chlorophenylalanine or 5-HT release was increased acutely in CIC-stressed rats with citalopram (5 mg/kg, s.c.) given 30 min prior to the first reversal task. Microdialysis was used to assess CIC-induced changes in 5-HT release in OFC during testing.

Results: CIC-stressed rats exhibited a selective impairment on the first reversal task in the AST. 5-HT depletion induced a similarly selective deficit in reversal learning. The CIC-induced impairment in reversal learning was attenuated by acute 5-HT reuptake blockade. 5-HT release was reduced in OFC of CIC-stressed rats during behavioral testing.

Conclusions: The CIC stress-induced impairment of cognitive flexibility may involve dysregulation of 5-HT modulatory function in OFC. Such deficits may thus model relevant symptoms of neuropsychiatric disorders that respond positively to SSRI treatment.

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Figures

Figure 1

Effects of 14-day CIC stress exposure on the mean trials to criterion for each stage of the AST (n = 12 per group). 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 control rats on the same stage; +p < 0.05 compared to other tasks for the same group).

Figure 2

Effects of PCPA pretreatment (4 × 200 mg/kg/day) on performance of rats on the AST (n = 9–11 per group). PCPA-treated rats required significantly more trials to reach criterion on the R1 reversal task compared to vehicle-treated controls (*p < 0.001 compared to control rats on the same stage; +p < 0.001 compared to other tasks for the same group).

Figure 3

Effect of acute citalopram treatment (5mg/kg, s.c.), given 30 min prior to testing on the R1 task, on the reversal deficit induced by 14-day CIC stress exposure. Only data from the R1 stage on, i.e., after drug injection, are shown. As in experiment 1, vehicle-treated CIC-stressed rats required significantly more trials to reach criterion on the R1 reversal stage compared to vehicle-treated non-stressed control rats, and also compared to CIC-stressed rats given an acute injection of citalopram. Note that in this experiment, CIC stress also induced a deficit in the third reversal task (R3), that was similarly reversed by citalopram. Citalopram-treated CIC-stressed rats did not differ from non-stressed vehicle-treated control rats on any test stage. (*p < 0.05 vehicle-treated rats, CIC-stressed compared to non-stressed controls; +p < 0.05 CIC-stressed rats, vehicle-treated compared to citalopram-treated; n = 10–11 per group).

Figure 4

Effects of 14-day CIC stress exposure on reversal learning and on extracellular 5-HT levels measured in OFC during behavioral testing on the AST. a) In replication of experiment 1, CIC-stressed rats required more trials to reach criterion during R1 compared to controls (n= 11–13 per group; *p < 0.05 compared to control rats on the same stage; +p < 0.05 compared to other tasks for the same group). b) Extracellular 5-HT levels, collected in OFC by microdialysis during behavioral testing, were reduced in CIC-stressed rats compared to control rats (n = 9 per group; p < 0.05 main effect of CIC stress compared to control).

References

1. Ahlers ST, Thomas JR, Berkey DL. Hippocampal and body temperature changes in rats during delayed matching-to-sample performance in a cold environment. Physiol Behav. 1991;50:1013–1018. - PubMed
1. Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nature Neurosci. 2005;8:365–371. - PubMed
1. Anisman H, Zacharko RM. Behavioral and neurochemical consequences associated with stressors. Ann N Y Acad Sci. 1986;467:205–225. - PubMed
1. Arnsten AFT, Li B-M. Neurobiology of executive functions: Catecholamine influences on prefrontal cortical functions. Biol Psychiatry. 2005;57:1377–1384. - PubMed
1. Beck AT. Cognitive therapy and the emotional disorders. Int. Univ. Press, Int. Univ. Press; 1976.

Chronic intermittent cold stress and serotonin depletion induce deficits of reversal learning in an attentional set-shifting test in rats - PubMed (original) (raw)