Review Personality, Addiction, Dopamine: Insights from Parkinson's Disease Table 1. Possible Site of Striatal Dopamine Dysfunction Causing Different Motor and Cognitive Symptoms in Parkinson's Disease

In rare instances, patients with Parkinson's disease (PD) may become addicted to their own medication or develop behavioral addictions such as pathological gambling. This is surprising because PD patients typically have a very low incidence of drug abuse and display a personality type that is the polar opposite of the addictive personality. These rare addictive syndromes, which appear to result from excessive dopami-nergic medication use, illustrate the link between dopamine, personality, and addiction. We describe the clinical phenomena and attempt to relate them to current models of learning and addiction. We conclude that persistently elevated dopaminergic stimulation promotes the development and maintenance of addic-tive behaviors. Introduction James Parkinson's essay on the shaking palsy notably described a movement disorder with ''the senses and the intellect being uninjured''; however, Parkinson's disease (PD) also consists of cognitive, behavioral, and mood symptoms, which are now being recognized as a major source of disability. The movement disorder, which is due to dopamine deficiency in the motor subdivision of the striatum, responds well to the dopamine precursor levodopa and to dopamine agonists such as pramipexole and ropinirole. However, recently, a constellation of addictive syndromes has been noticed in certain patients: addiction to one's medications, compulsive behaviors, and behavioral addictions such as pathological gambling, compulsive shopping, or hyper-sexuality. These syndromes are side-effects of the medications used to treat PD and are now thought to be a consequence of excessive dopaminergic stimulation. Addiction can be viewed as a disorder of decision making, learning, and motivation (Berke and Hyman, 2000), and dopa-mine acting on cortico-striatal neurons is normally involved in all of these phenomena. More specifically, the known role of dopamine in reward learning and reinforcement provides a mechanism by which the repeated use of addictive drugs can eventually become compulsive and habitual. Most addictive drugs release dopamine in the brain, and lesions of the dopamine system attenuate their reinforcing effects (Robbins and Everitt, 1999). Wise suggested that addictive drugs exert their reinforcing effects by acting on dopaminergic brain circuitry that normally processes natural rewards such as food and sex (Wise and Rompre, 1989). Questions remain however. By what mechanism does dopa-mine promote learning and reinforcement? Is dopamine also involved in maintaining the addictive behavior in the face of negative consequences? Are there pre-existing abnormalities in the dopamine system that confer vulnerability to addiction, and is there such a thing as an addictive personality? What is the importance of …

[1]  F. Manes,et al.  Frontotemporal dementia presenting as pathological gambling , 2010, Nature Reviews Neurology.

[2]  Michael X. Cohen,et al.  Neurocomputational models of basal ganglia function in learning, memory and choice , 2009, Behavioural Brain Research.

[3]  Andrew D. Blackwell,et al.  The Effects of Methylphenidate on Decision Making in Attention-Deficit/Hyperactivity Disorder , 2008, Biological Psychiatry.

[4]  P. Greengard,et al.  Dichotomous Dopaminergic Control of Striatal Synaptic Plasticity , 2008, Science.

[5]  Trevor W. Robbins,et al.  High Impulsivity Predicts the Switch to Compulsive Cocaine-Taking , 2008, Science.

[6]  A. Siderowf,et al.  Long‐term follow‐up of impulse control disorders in Parkinson's disease , 2008, Movement disorders : official journal of the Movement Disorder Society.

[7]  M. Reuter,et al.  Genetically Determined Differences in Learning from Errors , 2007, Science.

[8]  P. Seeman.  Antiparkinson therapeutic potencies correlate with their affinities at dopamine D2High receptors , 2007, Synapse.

[9]  P. Glimcher,et al.  The neural correlates of subjective value during intertemporal choice , 2007, Nature Neuroscience.

[10]  Michael J. Frank,et al.  Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning , 2007, Proceedings of the National Academy of Sciences.

[11]  Andrew J Lees,et al.  Pathological gambling in Parkinson's disease: Risk factors and differences from dopamine dysregulation. An analysis of published case series , 2007, Movement disorders : official journal of the Movement Disorder Society.

[12]  P. Glimcher,et al.  Statistics of midbrain dopamine neuron spike trains in the awake primate. , 2007, Journal of neurophysiology.

[13]  R. Wightman,et al.  Coordinated Accumbal Dopamine Release and Neural Activity Drive Goal-Directed Behavior , 2007, Neuron.

[14]  P. Dayan,et al.  Tonic dopamine: opportunity costs and the control of response vigor , 2007, Psychopharmacology.

[15]  Young T. Hong,et al.  Nucleus Accumbens D2/3 Receptors Predict Trait Impulsivity and Cocaine Reinforcement , 2007, Science.

[16]  T. Robbins,et al.  A role for mesencephalic dopamine in activation: commentary on Berridge (2006) , 2007, Psychopharmacology.

[17]  K. Berridge.  The debate over dopamine’s role in reward: the case for incentive salience , 2007, Psychopharmacology.

[18]  A. Lang,et al.  Factors associated with dopaminergic drug-related pathological gambling in Parkinson disease. , 2007, Archives of neurology.

[19]  M. Silber,et al.  Pathologic gambling in patients with restless legs syndrome treated with dopaminergic agonists , 2007, Neurology.

[20]  A. Hariri,et al.  Preference for Immediate over Delayed Rewards Is Associated with Magnitude of Ventral Striatal Activity , 2006, The Journal of Neuroscience.

[21]  Alain Dagher,et al.  Modeling sensitization to stimulants in humans: an [11C]raclopride/positron emission tomography study in healthy men. , 2006, Archives of general psychiatry.

[22]  S. Bassett,et al.  Clinical features associated with impulse control disorders in Parkinson disease , 2006, Neurology.

[23]  R. Dolan,et al.  Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans , 2006, Nature.

[24]  M. Potenza.  Should addictive disorders include non-substance-related conditions? , 2006, Addiction.

[25]  P. Shizgal,et al.  Prolonged rewarding stimulation of the rat medial forebrain bundle: neurochemical and behavioral consequences. , 2006, Behavioral neuroscience.

[26]  L. Vanderschuren,et al.  Critical Involvement of Dopaminergic Neurotransmission in Impulsive Decision Making , 2006, Biological Psychiatry.

[27]  P. Moberg,et al.  Association of dopamine agonist use with impulse control disorders in Parkinson disease. , 2006, Archives of neurology.

[28]  Yen F. Tai,et al.  Compulsive drug use linked to sensitized ventral striatal dopamine transmission , 2006, Annals of neurology.

[29]  S. Killcross,et al.  Amphetamine Exposure Enhances Habit Formation , 2006, The Journal of Neuroscience.

[30]  T. Robbins,et al.  Methylphenidate (‘Ritalin’) can Ameliorate Abnormal Risk-Taking Behavior in the Frontal Variant of Frontotemporal Dementia , 2006, Neuropsychopharmacology.

[31]  Joseph M. Tonning,et al.  Association between pathologic gambling and parkinsonian therapy as detected in the Food and Drug Administration Adverse Event database. , 2006, Archives of neurology.

[32]  S. W. Kim,et al.  Nucleus accumbens dopamine release is necessary and sufficient to promote the behavioral response to reward-predictive cues , 2005, Neuroscience.

[33]  A. Lawrence,et al.  Factors influencing susceptibility to compulsive dopaminergic drug use in Parkinson disease , 2005, Neurology.

[34]  T. Robbins,et al.  Neural systems of reinforcement for drug addiction: from actions to habits to compulsion , 2005, Nature Neuroscience.

[35]  E. Englund,et al.  Psychiatric Symptoms and Their Psychosocial Consequences in Frontotemporal Dementia , 2005, Alzheimer disease and associated disorders.

[36]  P. Sokoloff,et al.  The dopamine D3 receptor and drug dependence: Effects on reward or beyond? , 2005, Neuropharmacology.

[37]  Y. Geda,et al.  Pathological gambling caused by drugs used to treat Parkinson disease. , 2005, Archives of Neurology.

[38]  A J Lees,et al.  Relationship between impulsive sensation seeking traits, smoking, alcohol and caffeine intake, and Parkinson’s disease , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[39]  Merja Haaparanta,et al.  The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L-amino acid decarboxylase in healthy subjects , 2005, Pharmacogenetics and genomics.

[40]  A. Grace,et al.  Dopaminergic modulation of limbic and cortical drive of nucleus accumbens in goal-directed behavior , 2005, Nature Neuroscience.

[41]  J. Salamone,et al.  Beyond the reward hypothesis: alternative functions of nucleus accumbens dopamine. , 2005, Current opinion in pharmacology.

[42]  R. Palmiter,et al.  Distinguishing whether dopamine regulates liking, wanting, and/or learning about rewards. , 2005, Behavioral neuroscience.

[43]  Michael J. Frank,et al.  By Carrot or by Stick: Cognitive Reinforcement Learning in Parkinsonism , 2004, Science.

[44]  Samuel M. McClure,et al.  Separate Neural Systems Value Immediate and Delayed Monetary Rewards , 2004, Science.

[45]  J. W. Aldridge,et al.  Hyperdopaminergic mutant mice have higher "wanting" but not "liking" for sweet rewards. , 2004, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[46]  B. Knowlton,et al.  An implicit learning task activates medial temporal lobe in patients with Parkinson's disease. , 2004, Behavioral neuroscience.

[47]  I. McKeith,et al.  Cerebral atrophy in Parkinson's disease with and without dementia: a comparison with Alzheimer's disease, dementia with Lewy bodies and controls. , 2004, Brain : a journal of neurology.

[48]  T. Robbins,et al.  l-Dopa medication remediates cognitive inflexibility, but increases impulsivity in patients with Parkinson’s disease , 2003, Neuropsychologia.

[49]  M. Stacy,et al.  Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease , 2003, Neurology.

[50]  Samuel M. McClure,et al.  A computational substrate for incentive salience , 2003, Trends in Neurosciences.

[51]  R. Wightman,et al.  Subsecond dopamine release promotes cocaine seeking , 2003, Nature.

[52]  A. Dagher,et al.  Amphetamine-Induced Increases in Extracellular Dopamine, Drug Wanting, and Novelty Seeking: A PET/[11C]Raclopride Study in Healthy Men , 2002, Neuropsychopharmacology.

[53]  Rita Z. Goldstein,et al.  Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. , 2002, The American journal of psychiatry.

[54]  J. O'Doherty,et al.  Neural Responses during Anticipation of a Primary Taste Reward , 2002, Neuron.

[55]  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.

[56]  Suck-Won Kim,et al.  Personality dimensions in pathological gambling disorder and obsessive–compulsive disorder , 2001, Psychiatry Research.

[57]  T. Robbins,et al.  Impulsive Choice Induced in Rats by Lesions of the Nucleus Accumbens Core , 2001, Science.

[58]  Thomas J. H. Chen,et al.  The Reward Deficiency Syndrome: A Biogenetic Model for the Diagnosis and Treatment of Impulsive, Addictive and Compulsive Behaviors , 2000, Journal of psychoactive drugs.

[59]  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.

[60]  A. Lees,et al.  Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies , 2000, Journal of neurology, neurosurgery, and psychiatry.

[61]  S. Hyman,et al.  Addiction, Dopamine, and the Molecular Mechanisms of Memory , 2000, Neuron.

[62]  JaneR . Taylor,et al.  Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli , 1999, Psychopharmacology.

[63]  B. Everitt,et al.  Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist , 1999, Nature.

[64]  T. Robbins,et al.  Drug addiction: bad habits add up , 1999, Nature.

[65]  P. Garris,et al.  Dissociation of dopamine release in the nucleus accumbens from intracranial self-stimulation , 1999, Nature.

[66]  P. Sokoloff,et al.  Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[67]  S. Gilman,et al.  Presynaptic monoaminergic vesicles in Parkinson's disease and normal aging , 1996, Annals of neurology.

[68]  J. Mink.  THE BASAL GANGLIA: FOCUSED SELECTION AND INHIBITION OF COMPETING MOTOR PROGRAMS , 1996, Progress in Neurobiology.

[69]  M. Piercey,et al.  Inhibition of dopamine neuron firing by pramipexole, a dopamine D3 receptor-preferring agonist: comparison to other dopamine receptor agonists. , 1996, European journal of pharmacology.

[70]  A. Levey,et al.  Differential changes in neurochemical markers of striatal dopamine nerve terminals in idiopathic Parkinson's disease , 1996, Neurology.

[71]  D. Comings,et al.  A study of the dopamine D2 receptor gene in pathological gambling. , 1996, Pharmacogenetics.

[72]  P. Dayan,et al.  A framework for mesencephalic dopamine systems based on predictive Hebbian learning , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[73]  T. Robinson,et al.  Amphetamine‐Induced time‐dependent sensitization of dopamine neurotransmission in the dorsal and ventral striatum: A microdialysis study in behaving rats , 1995, Synapse.

[74]  A. Parent.  Extrinsic connections of the basal ganglia , 1990, Trends in Neurosciences.

[75]  J. Penney,et al.  The functional anatomy of basal ganglia disorders , 1989, Trends in Neurosciences.

[76]  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.

[77]  A. Lees,et al.  The pre-morbid personality of patients with Parkinson's disease. , 1985, Journal of neurology, neurosurgery, and psychiatry.

[78]  Anthony A Grace,et al.  Physiology of the normal and dopamine‐depleted basal ganglia: Insights into levodopa pharmacotherapy , 2008, Movement disorders : official journal of the Movement Disorder Society.

[79]  T. Robbins,et al.  L-DOPA Disrupts Activity in the Nucleus Accumbens during Reversal Learning in Parkinson's Disease , 2007, Neuropsychopharmacology.

[80]  W. Schultz.  Behavioral theories and the neurophysiology of reward. , 2006, Annual review of psychology.

[81]  T. Robbins,et al.  6-Hydroxydopamine lesions of the nucleus accumbens, but not of the caudate nucleus, attenuate enhanced responding with reward-related stimuli produced by intra-accumbens d-amphetamine , 2004, Psychopharmacology.

[82]  T. Robbins,et al.  Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens , 2004, Psychopharmacology.

[83]  R. Wise,et al.  Brain dopamine and reward. , 1989, Annual review of psychology.

[84]  C. Robert Cloninger.  A systematic method for clinical description and classification of personality variants. A proposal. , 1987, Archives of general psychiatry.