Cognitive inflexibility after prefrontal serotonin depletion is behaviorally and neurochemically specific.

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.

[1]  Charles M. Butter,et al.  Perseveration in extinction and in discrimination reversal tasks following selective frontal ablations in Macaca mulatta , 1969 .

[2]  D. Meyer,et al.  Assessment of the role of transfer suppression in learning-set formation in monkeys. , 1971 .

[3]  M. Mishkin,et al.  Limbic lesions and the problem of stimulus--reinforcement associations. , 1972, Experimental neurology.

[4]  N. Mackintosh.  The psychology of animal learning , 1974 .

[5]  G. E. Alexander,et al.  Parallel organization of functionally segregated circuits linking basal ganglia and cortex. , 1986, Annual review of neuroscience.

[6]  T. Robbins,et al.  The effects of intradimensional and extradimensional shifts on visual discrimination learning in humans and non-human primates , 1988, The Quarterly journal of experimental psychology. B, Comparative and physiological psychology.

[7]  S. Kish,et al.  Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications. , 1988, The New England journal of medicine.

[8]  C. Marsden,et al.  'Frontal' cognitive function in patients with Parkinson's disease 'on' and 'off' levodopa. , 1988, Brain : a journal of neurology.

[9]  Y Agid,et al.  Are dopaminergic neurons selectively vulnerable to Parkinson's disease? , 1993, Advances in neurology.

[10]  E. Rolls,et al.  Emotion-related learning in patients with social and emotional changes associated with frontal lobe damage. , 1994, Journal of neurology, neurosurgery, and psychiatry.

[11]  J. T. Coull,et al.  Tryptophan depletion in normal volunteers produces selective impairments in learning and memory , 1994, Neuropharmacology.

[12]  A C Roberts,et al.  6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: possible interactions with subcortical dopamine , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  L. Bellodi,et al.  Frontal-Lobe Dysfunction in Schizophrenia and Obsessive-Compulsive Disorder - A Neuropsychological Study , 1995, Brain and Cognition.

[14]  A C Roberts,et al.  Primate analogue of the Wisconsin Card Sorting Test: effects of excitotoxic lesions of the prefrontal cortex in the marmoset. , 1996, Behavioral neuroscience.

[15]  T. Robbins,et al.  Dissociation in prefrontal cortex of affective and attentional shifts , 1996, Nature.

[16]  C. Benkelfat,et al.  Tryptophan Depletion, Executive Functions, and Disinhibition in Aggressive, Adolescent Males , 1998, Neuropsychopharmacology.

[17]  M Freedman,et al.  Orbitofrontal function, object alternation and perseveration. , 1998, Cerebral cortex.

[18]  A L Brody,et al.  Neuroimaging and frontal-subcortical circuitry in obsessive-compulsive disorder , 1998, British Journal of Psychiatry.

[19]  S. Alborzian,et al.  Localized Orbitofrontal and Subcortical Metabolic Changes and Predictors of Response to Paroxetine Treatment in Obsessive-Compulsive Disorder , 1999, Neuropsychopharmacology.

[20]  C. Benkelfat,et al.  Behavioral disinhibition induced by tryptophan depletion in nonalcoholic young men with multigenerational family histories of paternal alcoholism. , 1999, The American journal of psychiatry.

[21]  T. Robbins,et al.  Comparison of set-shifting ability in patients with chronic schizophrenia and frontal lobe damage , 1999, Schizophrenia Research.

[22]  T. Robbins,et al.  Tryptophan depletion impairs stimulus-reward learning while methylphenidate disrupts attentional control in healthy young adults: implications for the monoaminergic basis of impulsive behaviour , 1999, Psychopharmacology.

[23]  S. Klein,et al.  Handbook of contemporary learning theories , 2000 .

[24]  T. Robbins,et al.  Contrasting Cortical and Subcortical Activations Produced by Attentional-Set Shifting and Reversal Learning in Humans , 2000, Journal of Cognitive Neuroscience.

[25]  T. Robbins,et al.  Probabilistic learning and reversal deficits in patients with Parkinson’s disease or frontal or temporal lobe lesions: possible adverse effects of dopaminergic medication , 2000, Neuropsychologia.

[26]  R. Elliott,et al.  Dissociable functions in the medial and lateral orbitofrontal cortex: evidence from human neuroimaging studies. , 2000, Cerebral cortex.

[27]  T. Robbins,et al.  Differential effects of 6-OHDA lesions of the frontal cortex and caudate nucleus on the ability to acquire an attentional set. , 2001, Cerebral cortex.

[28]  E. Rolls,et al.  Abstract reward and punishment representations in the human orbitofrontal cortex , 2001, Nature Neuroscience.

[29]  Alan C. Evans,et al.  Changes in brain activity related to eating chocolate: from pleasure to aversion. , 2001, Brain : a journal of neurology.

[30]  T. Robbins,et al.  Enhanced or impaired cognitive function in Parkinson's disease as a function of dopaminergic medication and task demands. , 2001, Cerebral cortex.

[31]  Peter Olausson,et al.  Impairments of Reversal Learning and Response Perseveration after Repeated, Intermittent Cocaine Administrations to Monkeys , 2002, Neuropsychopharmacology.

[32]  W. Schultz.  Getting Formal with Dopamine and Reward , 2002, Neuron.

[33]  Harriet de Wit,et al.  Effect of tryptophan depletion on impulsive behavior in men with or without a family history of alcoholism , 2002, Behavioural Brain Research.

[34]  B. Everitt,et al.  Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex , 2002, Neuroscience & Biobehavioral Reviews.

[35]  R. Oades,et al.  Serotonin Platelet-Transporter Measures in Childhood Attention-Deficit/Hyperactivity Disorder (ADHD): Clinical versus Experimental Measures of Impulsivity , 2002, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[36]  U. Hadar,et al.  Perseveration and over-switching in schizophrenia , 2003, Schizophrenia Research.

[37]  Yasuhiro Kaneda,et al.  Serotonin receptors : their key role in drugs to treat schizophrenia , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[38]  J. Deakin,et al.  Effects of orbital prefrontal cortex dopamine depletion on inter-temporal choice: a quantitative analysis , 2004, Psychopharmacology.

[39]  T. Robbins,et al.  Cognitive Inflexibility After Prefrontal Serotonin Depletion , 2004, Science.

[40]  E. Rolls,et al.  Reward-related Reversal Learning after Surgical Excisions in Orbito-frontal or Dorsolateral Prefrontal Cortex in Humans , 2004, Journal of Cognitive Neuroscience.

[41]  Trevor W Robbins,et al.  Fractionating Impulsivity: Contrasting Effects of Central 5-HT Depletion on Different Measures of Impulsive Behavior , 2004, Neuropsychopharmacology.

[42]  Michael Koch,et al.  Dopamine in the orbitofrontal cortex regulates operant responding under a progressive ratio of reinforcement in rats , 2004, Neuroscience Letters.

[43]  T. Robbins,et al.  Limbic Corticostriatal Systems and Delayed Reinforcement , 2004, Annals of the New York Academy of Sciences.

[44]  M. Mishkin,et al.  Perseverative interference in monkeys following selective lesions of the inferior prefrontal convexity , 1970, Experimental Brain Research.

[45]  C. Marsden,et al.  l-Dopa withdrawal in Parkinson's disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction , 2005, Psychopharmacology.

[46]  T. Robbins,et al.  Stop signal response inhibition is not modulated by tryptophan depletion or the serotonin transporter polymorphism in healthy volunteers: implications for the 5-HT theory of impulsivity , 2005, Psychopharmacology.

[47]  T. Robbins,et al.  Prefrontal Serotonin Depletion Affects Reversal Learning But Not Attentional Set Shifting , 2005, The Journal of Neuroscience.

[48]  T. Robbins,et al.  Serotonergic Modulation of Prefrontal Cortex during Negative Feedback in Probabilistic Reversal Learning , 2005, Neuropsychopharmacology.

[49]  T. Robbins,et al.  Double dissociation between serotonergic and dopaminergic modulation of medial prefrontal and orbitofrontal cortex during a test of impulsive choice. , 2006, Cerebral cortex.

[50]  R. Cools.  Dopaminergic modulation of cognitive function-implications for l-DOPA treatment in Parkinson's disease , 2006, Neuroscience & Biobehavioral Reviews.