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

Psychopharmacology (Berl). 2009 Jan;202(1-3):329-41. doi: 10.1007/s00213-008-1224-6. Epub 2008 Jun 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Attention / drug effects*
  • Chronic Disease
  • Citalopram / pharmacology
  • Cold Temperature*
  • Discrimination Learning / physiology
  • Fenclonine / pharmacology
  • Learning Disabilities / etiology*
  • Learning Disabilities / psychology*
  • Male
  • Odorants
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / physiology
  • Psychomotor Performance / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Reversal Learning / physiology*
  • Serotonin / metabolism
  • Serotonin / physiology*
  • Serotonin Agents / pharmacology
  • Serotonin Uptake Inhibitors / pharmacology
  • Set, Psychology*
  • Stress, Psychological / physiopathology*


  • Serotonin Agents
  • Serotonin Uptake Inhibitors
  • Citalopram
  • Serotonin
  • Fenclonine