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Monoamine Levels Within the Orbitofrontal Cortex and Putamen Interact to Predict Reversal Learning Performance

      Background

      The compulsive and inflexible behaviors that are present in many psychiatric disorders, particularly behavioral addictions and obsessive-compulsive disorder, may be due to neurochemical dysfunction within the circuitry that enables goal-directed behaviors. Experimental removal of serotonin or dopamine within the orbitofrontal cortex or dorsal striatum, respectively, impairs flexible responding in a reversal learning test, suggesting that these neurochemical systems exert important modulatory influences on goal-directed behaviors. Nevertheless, the behavioral impairments present in psychiatric disorders are likely due to subtle neurochemical differences, and it remains unknown whether naturally occurring variation in neurochemical levels associate with individual differences in flexible, reward-directed behaviors.

      Methods

      The current study assessed the ability of 24 individual juvenile monkeys to acquire, retain, and reverse discrimination problems and examined whether monoamine levels in the orbitofrontal cortex, caudate nucleus, and putamen could explain variance in behavior.

      Results

      The interaction between dopamine levels in the putamen and serotonin levels in the orbitofrontal cortex explained 61% of the variance in a measure of behavioral flexibility but not measures of associative learning or memory. The interaction mirrored that of a hyperbolic function, with reversal learning performance being poorest in either monkeys with relatively low levels of orbitofrontal serotonin and putamen dopamine or in monkeys with relatively high levels of orbitofrontal serotonin and putamen dopamine levels.

      Conclusions

      These results support the hypothesis that subcortical and cortical neuromodulatory systems interact to guide aspects of goal-directed behavior, providing insight into the neurochemical dysfunction that may underlie the inflexible and compulsive behaviors present in psychiatric disorders.

      Key Words

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      References

        • Ghahremani D.G.
        • Tabibnia G.
        • Monterosso J.
        • Hellemann G.
        • Poldrack R.A.
        • London E.D.
        Effect of modafinil on learning and task-related brain activity in methamphetamine-dependent and healthy individuals.
        Neuropsychopharmacology. 2011; 36 (:950–359)
        • Ersche K.D.
        • Roiser J.P.
        • Robbins T.W.
        • Sahakian B.J.
        Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans.
        Psychopharmacology (Berl). 2008; 197: 421-431
        • Valerius G.
        • Lumpp A.
        • Kuelz A.K.
        • Freyer T.
        • Voderholzer U.
        Reversal learning as a neuropsychological indicator for the neuropathology of obsessive compulsive disorder? A behavioral study.
        J Neuropsychiatry Clin Neurosci. 2008; 20: 210-218
        • Thompson P.M.
        • Hayashi K.M.
        • Simon S.L.
        • Geaga J.A.
        • Hong M.S.
        • Sui Y.
        • et al.
        Structural abnormalities in the brains of human subjects who use methamphetamine.
        J Neurosci. 2004; 24: 6028-6036
        • Chamberlain S.R.
        • Menzies L.
        • Hampshire A.
        • Suckling J.
        • Fineberg N.A.
        • del Campo N.
        • et al.
        Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives.
        Science. 2008; 321: 421-422
        • Butter C.M.
        • Mishkin M.
        • Rosvold H.E.
        Conditioning and extinction of a food-rewarded response after selective ablations of frontal cortex in rhesus monkeys.
        Exp Neurol. 1963; 7: 65-75
        • Dias R.
        • Robbins T.W.
        • Roberts A.C.
        Dissociation in prefrontal cortex of affective and attentional shifts.
        Nature. 1996; 380: 69-72
        • Fellows L.K.
        • Farah M.J.
        Ventromedial frontal cortex mediates affective shifting in humans: Evidence from a reversal learning paradigm.
        Brain. 2003; 126: 1830-1837
        • Ghahremani D.G.
        • Monterosso J.
        • Jentsch J.D.
        • Bilder R.M.
        • Poldrack R.A.
        Neural components underlying behavioral flexibility in human reversal learning.
        Cereb Cortex. 2010; 20: 1843-1852
        • Selemon L.D.
        • Goldman-Rakic P.S.
        Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey.
        J Neurosci. 1985; 5: 776-794
        • Haber S.N.
        • Kim K.S.
        • Mailly P.
        • Calzavara R.
        Reward-related cortical inputs define a large striatal region in primates that interface with associative cortical connections, providing a substrate for incentive-based learning.
        J Neurosci. 2006; 26: 8368-8376
        • Yin H.H.
        • Ostlund S.B.
        • Knowlton B.J.
        • Balleine B.W.
        The role of the dorsomedial striatum in instrumental conditioning.
        Eur J Neurosci. 2005; 22: 513-523
        • Yin H.H.
        • Knowlton B.J.
        • Balleine B.W.
        Inactivation of dorsolateral striatum enhances sensitivity to changes in the action-outcome contingency in instrumental conditioning.
        Behav Brain Res. 2006; 166: 189-196
        • Castane A.
        • Theobald D.E.
        • Robbins T.W.
        Selective lesions of the dorsomedial striatum impair serial spatial reversal learning in rats.
        Behav Brain Res. 2010; 210: 74-83
        • Divac I.
        • Rosvold H.E.
        • Szwarcbart M.K.
        Behavioral effects of selective ablation of the caudate nucleus.
        J Comp Physiol Psychol. 1967; 63: 184-190
        • Clarke H.F.
        • Robbins T.W.
        • Roberts A.C.
        Lesions of the medial striatum in monkeys produce perseverative impairments during reversal learning similar to those produced by lesions of the orbitofrontal cortex.
        J Neurosci. 2008; 28: 10972-10982
        • Freyer T.
        • Valerius G.
        • Kuelz A.K.
        • Speck O.
        • Glauche V.
        • Hull M.
        • Voderholzer U.
        Test-retest reliability of event-related functional MRI in a probabilistic reversal learning task.
        Psychiatry Res. 2009; 174: 40-46
        • Clarke H.F.
        • Dalley J.W.
        • Crofts H.S.
        • Robbins T.W.
        • Roberts A.C.
        Cognitive inflexibility after prefrontal serotonin depletion.
        Science. 2004; 304: 878-880
        • Clarke H.F.
        • Hill G.J.
        • Robbins T.W.
        • Roberts A.C.
        Dopamine, but not serotonin, regulates reversal learning in the marmoset caudate nucleus.
        J Neurosci. 2011; 31: 4290-4297
        • Peterson D.A.
        • Elliott C.
        • Song D.D.
        • Makeig S.
        • Sejnowski T.J.
        • Poizner H.
        Probabilistic reversal learning is impaired in Parkinson's disease.
        Neuroscience. 2009; 163: 1092-1101
        • Sahakian B.J.
        • Sarna G.S.
        • Kantamaneni B.D.
        • Jackson A.
        • Hutson P.H.
        • Curzon G.
        Association between learning and cortical catecholamines in non-drug-treated rats.
        Psychopharmacology (Berl). 1985; 86: 339-343
        • Groman S.M.
        • Lee B.
        • London E.D.
        • Mandelkern M.A.
        • James A.S.
        • Feiler K.
        • et al.
        Dorsal striatal D2-like receptor availability covaries with sensitivity to positive reinforcement during discrimination learning.
        J Neurosci. 2011; 31: 7291-7299
        • Groman S.M.
        • Lee B.
        • Seu E.
        • James A.S.
        • Feiler K.
        • Mandelkern M.A.
        • et al.
        Dysregulation of d2-mediated dopamine transmission in monkeys after chronic escalating methamphetamine exposure.
        J Neurosci. 2012; 32: 5843-5852
        • Jentsch J.D.
        • Tran A.
        • Le D.
        • Youngren K.D.
        • Roth R.H.
        Subchronic phencyclidine administration reduces mesoprefrontal dopamine utilization and impairs prefrontal cortical-dependent cognition in the rat.
        Neuropsychopharmacology. 1997; 17: 92-99
        • Lowry O.H.
        • Rosebrough N.J.
        • Farr A.L.
        • Randall R.J.
        Protein measurement with the Folin phenol reagent.
        J Biol Chem. 1951; 193: 265-275
        • O'Neill M.
        • Brown V.J.
        The effect of striatal dopamine depletion and the adenosine A2A antagonist KW-6002 on reversal learning in rats.
        Neurobiol Learn Mem. 2007; 88: 75-81
        • Clatworthy P.L.
        • Lewis S.J.
        • Brichard L.
        • Hong Y.T.
        • Izquierdo D.
        • Clark L.
        • et al.
        Dopamine release in dissociable striatal subregions predicts the different effects of oral methylphenidate on reversal learning and spatial working memory.
        J Neurosci. 2009; 29: 4690-4696
        • Haber S.N.
        The primate basal ganglia: Parallel and integrative networks.
        J Chem Neuroanat. 2003; 26: 317-330
        • Chudasama Y.
        • Daniels T.E.
        • Gorrin D.P.
        • Rhodes S.E.
        • Rudebeck P.H.
        • Murray E.A.
        The role of the anterior cingulate cortex in choices based on reward value and reward contingency [published online ahead of print September 3].
        Cereb Cortex. 2012;
        • Iversen S.D.
        • Mishkin M.
        Perseverative interference in monkeys following selective lesions of the inferior prefrontal convexity.
        Exp Brain Res. 1970; 11: 376-386
        • Rudebeck P.H.
        • Murray E.A.
        Amygdala and orbitofrontal cortex lesions differentially influence choices during object reversal learning.
        J Neurosci. 2008; 28: 8338-8343
        • Mendlin A.
        • Martin F.J.
        • Jacobs B.L.
        Dopaminergic input is required for increases in serotonin output produced by behavioral activation: An in vivo microdialysis study in rat forebrain.
        Neuroscience. 1999; 93: 897-905
        • Leggio G.M.
        • Cathala A.
        • Moison D.
        • Cunningham K.A.
        • Piazza P.V.
        • Spampinato U.
        Serotonin 2C receptors in the medial prefrontal cortex facilitate cocaine-induced dopamine release in the rat nucleus accumbens.
        Neuropharmacology. 2009; 56: 507-513
        • Lee B.
        • London E.D.
        • Poldrack R.A.
        • Farahi J.
        • Nacca A.
        • Monterosso J.R.
        • et al.
        Striatal dopamine d2/d3 receptor availability is reduced in methamphetamine dependence and is linked to impulsivity.
        J Neurosci. 2009; 29: 14734-14740
        • Boulougouris V.
        • Robbins T.W.
        Enhancement of spatial reversal learning by 5-HT2C receptor antagonism is neuroanatomically specific.
        J Neurosci. 2010; 30: 930-938
        • Brigman J.L.
        • Mathur P.
        • Harvey-White J.
        • Izquierdo A.
        • Saksida L.M.
        • Bussey T.J.
        • et al.
        Pharmacological or genetic inactivation of the serotonin transporter improves reversal learning in mice.
        Cereb Cortex. 2010; 20: 1955-1963
        • Paxinos G.
        • Huang X.-F.
        • Toga A.W.
        The Rhesus Monkey Brain in Stereotaxic Coordinates.
        Academic Press, San Diego2009