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Cerebral Cortex Advance Access first published online on February 15, 2006
This version published online on February 20, 2006
Cerebral Cortex, doi:10.1093/cercor/bhj120
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Article

Cognitive Inflexibility after Prefrontal Serotonin Depletion Is Behaviorally and Neurochemically Specific

H.F. Clarke 1 *, S.C. Walker 1, J.W. Dalley 1, T.W. Robbins 1, and A.C. Roberts 2

1 Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK; Cambridge University Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK
2 Department of Anatomy, University of Cambridge, Downing Street, Cambridge, CB2 3DY, UK; Cambridge University Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK

* To whom correspondence should be addressed.
H.F. Clarke, E-mail: hfc23{at}cam.ac.uk


  Abstract

We have previously demonstrated that prefrontal serotonin depletion impairs orbitofrontal cortex (OFC)-mediated serial discrimination reversal (SDR) learning but not lateral prefrontal cortex (PFC)-mediated attentional set shifting. To address the neurochemical specificity of this reversal deficit, Experiment 1 compared the effects of selective serotonin and selective dopamine depletions of the OFC on performance of the SDR task. Whereas serotonin depletions markedly impaired performance, OFC dopamine depletions were without effect. The behavioral specificity of this reversal impairment was investigated in Experiment 2 by examining the effect of OFC serotonin depletion on performance of a modified SDR task designed to distinguish between 3 possible causes of the impairment. The results showed that the reversal deficit induced by prefrontal serotonin depletion was not due to a failure to approach a previously unrewarded stimulus (enhanced learned avoidance) or reduced proactive interference. Instead, it was due specifically to a failure to inhibit responding to the previously rewarded stimulus. The neurochemical and behavioral specificity of this particular form of cognitive inflexibility is of particular relevance to our understanding of the aetiology and treatment of inflexible behavior apparent in many neuropsychiatric and neurodegenerative disorders involving the PFC.

Keywords: dopamine; marmoset; obsessive-compulsive disorder; orbitofrontal cortex; Parkinson's disease; reversal learning.
The following has been altered in this version: affiliations 2 and 3 have been transposed; in the abstract, dopamine in line 8 and serotonin in line 11 have been transposed; on page 3, (s-HIAA) has been corrected to (5-HIAA); on page 6, Figure 5's caption has been corrected to read "At all time points, the OFC and lateral PFC...".
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