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

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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 × 6 h/day at 4°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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Acknowledgments

We thank Ms. Julianne Doyen and Ms. Teresa F. Burke for expert technical assistance and also Dr. Dania Rossi for her input and assistance with the microdialysis experiments. The authors have no conflicts of interest to report or any involvement to disclose, financial or otherwise, that may bias the conduct, interpretation, or presentation of this work. All experiments were conducted in compliance with current law in the country in which they were performed.

Support was provided by a Young Investigator Award from NARSAD: The Mental Health Association (to MDSLB), and by research grants from the National Institutes of Health (MH53851 and MH72672 to DAM and MH52369 to JGH).

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Authors and Affiliations

  1. Department of Pharmacology, MC 7764, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA

    M. Danet S. Lapiz-Bluhm, Alexandra E. Soto-Piña, Julie G. Hensler & David A. Morilak

  2. Center for Biomedical Neuroscience, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA

    M. Danet S. Lapiz-Bluhm, Alexandra E. Soto-Piña, Julie G. Hensler & David A. Morilak

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  1. M. Danet S. Lapiz-Bluhm
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  2. Alexandra E. Soto-Piña
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  4. David A. Morilak
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Correspondence to David A. Morilak.

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Lapiz-Bluhm, M.D.S., Soto-Piña, A.E., Hensler, J.G. et al. Chronic intermittent cold stress and serotonin depletion induce deficits of reversal learning in an attentional set-shifting test in rats. Psychopharmacology 202, 329–341 (2009). https://doi.org/10.1007/s00213-008-1224-6

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