The D2/3 dopamine receptor in pathological gambling: a positron emission tomography study with [11C]-(+)-propyl-hexahydro-naphtho-oxazin and [11C]raclopride.

AIMS Pathological gambling (PG) shares diagnostic features with substance use disorder (SUD), but the neurochemical mechanisms underlying PG are poorly understood. Because dopamine (DA), a neurotransmitter implicated in reward and reinforcement, is probably involved, we used positron emission tomography (PET) to test whether PG is associated with abnormalities in D2 and D3 receptor levels, as observed in SUD. DESIGN Case-control study comparing PG to healthy control (HC) subjects. SETTING Academic research imaging centre. PARTICIPANTS Thirteen non-treatment-seeking males meeting DSM-IV criteria for PG, and 12 matched HC (11 of whom completed PET). MEASUREMENTS Two PET scans (one with the D3 receptor preferring agonist [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) and the other with [11C]raclopride) to assess D(2/3) DA receptor availability, and behavioural measures (self-report questionnaires and slot-machine game) to assess subjective effects and relationships to PET measures. FINDINGS Binding of both radiotracers did not differ between groups in striatum or substantia nigra (SN) (all P > 0.1). Across PG, [11C]-(+)-PHNO binding in SN, where the signal is attributable primarily to D3 receptors, correlated with gambling severity (r = 0.57, P = 0.04) and impulsiveness (r = 0.65, P = 0.03). In HC, [11C]raclopride binding in dorsal striatum correlated inversely with subjective effects of gambling (r = -0.70, P = 0.03) and impulsiveness (r = -0.70, P = 0.03). CONCLUSIONS Unlike with substance use disorder, there appear to be no marked differences in D2 /D3 levels between healthy subjects and pathological gamblers, suggesting that low receptor availability may not be a necessary feature of addiction. However, relationships between [11C]-(+)-PHNO binding and gambling severity/impulsiveness suggests involvement of the D3 receptor in impulsive/compulsive behaviours.

[1]  Thomas E. Nichols,et al.  Orbitofrontal connectivity with resting-state networks is associated with midbrain dopamine D3 receptor availability. , 2012, Cerebral cortex.

[2]  David J. Nutt,et al.  Striatal dopamine D2/D3 receptor binding in pathological gambling is correlated with mood-related impulsivity , 2012, NeuroImage.

[3]  M. Slifstein,et al.  Deficits in Dopamine D2 Receptors and Presynaptic Dopamine in Heroin Dependence: Commonalities and Differences with Other Types of Addiction , 2012, Biological Psychiatry.

[4]  Sylvain Houle,et al.  Higher Binding of the Dopamine D3 Receptor-Preferring Ligand [11C]-(+)-Propyl-Hexahydro-Naphtho-Oxazin in Methamphetamine Polydrug Users: A Positron Emission Tomography Study , 2012, The Journal of Neuroscience.

[5]  Marc Laruelle,et al.  Within-Subject Comparison of [11C]-( + )-PHNO and [11C]raclopride Sensitivity to Acute Amphetamine Challenge in Healthy Humans , 2012, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[6]  N. Volkow,et al.  Decreased dopamine activity predicts relapse in methamphetamine abusers , 2011, Molecular Psychiatry.

[7]  C. Mathis,et al.  Imaging of dopamine D2/3 agonist binding in cocaine dependence: A [11C]NPA positron emission tomography study , 2011, Synapse.

[8]  M. Zack,et al.  Haloperidol modifies instrumental aspects of slot machine gambling in pathological gamblers and healthy controls , 2011, Addiction biology.

[9]  Sang Hee Kim,et al.  Reduced striatal dopamine D2 receptors in people with Internet addiction , 2011, Neuroreport.

[10]  Mark Slifstein,et al.  Imaging dopamine transmission in cocaine dependence: link between neurochemistry and response to treatment. , 2011, The American journal of psychiatry.

[11]  Marios Politis,et al.  Cue-induced striatal dopamine release in Parkinson's disease-associated impulsive-compulsive behaviours. , 2011, Brain : a journal of neurology.

[12]  S. Cowlishaw,et al.  Prevalence of comorbid disorders in problem and pathological gambling: systematic review and meta-analysis of population surveys. , 2011, Addiction.

[13]  F. Vitaro,et al.  Predicting early gambling in children. , 2011, Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors.

[14]  A. Gjedde,et al.  Inverse association between dopaminergic neurotransmission and Iowa Gambling Task performance in pathological gamblers and healthy controls. , 2011, Scandinavian journal of psychology.

[15]  Arne Møller,et al.  Dopamine release in ventral striatum during Iowa Gambling Task performance is associated with increased excitement levels in pathological gambling. , 2011, Addiction.

[16]  Mark Jenkinson,et al.  Imaging dopamine receptors in humans with [11C]-(+)-PHNO: Dissection of D3 signal and anatomy , 2011, NeuroImage.

[17]  J. Kennedy,et al.  Association of functional variants in the dopamine D2-like receptors with risk for gambling behaviour in healthy Caucasian subjects , 2010, Biological Psychology.

[18]  D. Zald,et al.  Dopaminergic Network Differences in Human Impulsivity , 2010, Science.

[19]  C. Holden.  Psychiatry. Behavioral addictions debut in proposed DSM-V. , 2010, Science.

[20]  A. Newman,et al.  Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disorders , 2010, Annals of the New York Academy of Sciences.

[21]  Magnus Dahlbom,et al.  Striatal Dopamine D2/D3 Receptor Availability Is Reduced in Methamphetamine Dependence and Is Linked to Impulsivity , 2009, The Journal of Neuroscience.

[22]  Alan A. Wilson,et al.  Decreased binding of the D3 dopamine receptor-preferring ligand [11C]-(+)-PHNO in drug-naive Parkinson's disease. , 2009, Brain : a journal of neurology.

[23]  P. Seeman.  Dopamine D2High receptors measured ex vivo are elevated in amphetamine‐sensitized animals , 2009, Synapse.

[24]  T. Robbins,et al.  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 , 2022 .

[25]  M. Zack,et al.  Parallel roles for dopamine in pathological gambling and psychostimulant addiction. , 2009, Current drug abuse reviews.

[26]  S. Houle,et al.  Kinetics of [11C]-(+)-PHNO binding in the globus pallidus , 2008, NeuroImage.

[27]  C. Heidbreder.  Selective antagonism at dopamine D3 receptors as a target for drug addiction pharmacotherapy: a review of preclinical evidence. , 2008, CNS & neurological disorders drug targets.

[28]  M. Potenza,et al.  The neurobiology of pathological gambling and drug addiction: an overview and new findings , 2008, Philosophical Transactions of the Royal Society B: Biological Sciences.

[29]  T. Münte,et al.  Dopamine Agonist Increases Risk Taking but Blunts Reward-Related Brain Activity , 2008, PloS one.

[30]  Ariel Graff-Guerrero,et al.  Brain region binding of the D2/3 agonist [11C]‐(+)‐PHNO and the D2/3 antagonist [11C]raclopride in healthy humans , 2008, Human brain mapping.

[31]  Alan A. Wilson,et al.  First Human Evidence of d-Amphetamine Induced Displacement of a D2/3 Agonist Radioligand: A [11C]-(+)-PHNO Positron Emission Tomography Study , 2008, Neuropsychopharmacology.

[32]  R. P. Maguire,et al.  Consensus Nomenclature for in vivo Imaging of Reversibly Binding Radioligands , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[33]  J. Kennedy,et al.  Dopamine Genes and Pathological Gambling in Discordant Sib-Pairs , 2007, Journal of Gambling Studies.

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

[35]  M. Zack,et al.  A D2 Antagonist Enhances the Rewarding and Priming Effects of a Gambling Episode in Pathological Gamblers , 2007, Neuropsychopharmacology.

[36]  J. Kennedy,et al.  The Genetics of Gambling and Behavioral Addictions , 2006, CNS Spectrums.

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

[38]  Shitij Kapur,et al.  An automated method for the extraction of regional data from PET images , 2006, Psychiatry Research: Neuroimaging.

[39]  A. Lang,et al.  Prospective prevalence of pathologic gambling and medication association in Parkinson disease , 2006, Neurology.

[40]  Sylvain Houle,et al.  High-Affinity States of Human Brain Dopamine D2/3 Receptors Imaged by the Agonist [11C]-(+)-PHNO , 2006, Biological Psychiatry.

[41]  C. Nordin,et al.  CSF cholecystokinin, γ-aminobutyric acid and neuropeptide Y in pathological gamblers and healthy controls , 2006, Journal of Neural Transmission.

[42]  Mark Slifstein,et al.  Alcohol Dependence Is Associated with Blunted Dopamine Transmission in the Ventral Striatum , 2005, Biological Psychiatry.

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

[44]  Sylvain Houle,et al.  Radiosynthesis and evaluation of [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron emission tomography. , 2005, Journal of medicinal chemistry.

[45]  J. Gläscher,et al.  Pathological gambling is linked to reduced activation of the mesolimbic reward system , 2005, Nature Neuroscience.

[46]  Nora D. Volkow,et al.  The addicted human brain viewed in the light of imaging studies: brain circuits and treatment strategies , 2004, Neuropharmacology.

[47]  Nora D Volkow,et al.  Similarity Between Obesity and Drug Addiction as Assessed by Neurofunctional Imaging , 2004, Journal of addictive diseases.

[48]  Yiyun Huang,et al.  Cocaine Dependence and D2 Receptor Availability in the Functional Subdivisions of the Striatum: Relationship with Cocaine-Seeking Behavior , 2004, Neuropsychopharmacology.

[49]  R. Malenka,et al.  The addicted brain. , 2004, Scientific American.

[50]  Lia Nower,et al.  The relationship of impulsivity, sensation seeking, coping, and substance use in youth gamblers. , 2004, Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors.

[51]  M. Zack,et al.  Amphetamine Primes Motivation to Gamble and Gambling-Related Semantic Networks in Problem Gamblers , 2004, Neuropsychopharmacology.

[52]  C. Lejuez,et al.  Using the Rasch model to evaluate the South Oaks Gambling Screen for use with nonpathological gamblers. , 2003, Addictive behaviors.

[53]  P. Sokoloff,et al.  Increased dopamine D3 receptor expression accompanying behavioral sensitization to nicotine in rats , 2003, Synapse.

[54]  S. Kapur,et al.  Amphetamine‐sensitized animals show a marked increase in dopamine D2 high receptors occupied by endogenous dopamine, even in the absence of acute challenges , 2002, Synapse.

[55]  R. Stinchfield,et al.  Reliability, validity, and classification accuracy of the South Oaks Gambling Screen (SOGS). , 2002, Addictive behaviors.

[56]  J S Fowler,et al.  Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. , 2001, The American journal of psychiatry.

[57]  N. Volkow,et al.  Overexpression of dopamine D2 receptors reduces alcohol self‐administration , 2001, Journal of neurochemistry.

[58]  Nikolaus R. McFarland,et al.  Striatonigrostriatal Pathways in Primates Form an Ascending Spiral from the Shell to the Dorsolateral Striatum , 2000, The Journal of Neuroscience.

[59]  E. Noble,et al.  Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: a review , 2000, European Psychiatry.

[60]  P. Sokoloff,et al.  Dopamine D3 receptor agents as potential new medications for drug addiction , 2000, European Psychiatry.

[61]  N. Volkow,et al.  Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors. , 1999, The Journal of pharmacology and experimental therapeutics.

[62]  J S Fowler,et al.  Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels. , 1999, The American journal of psychiatry.

[63]  B. Cox,et al.  Characteristics of Problem Gambling in a Canadian Context: A Preliminary Study Using a DSM-IV-Based Questionnaire , 1999, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[64]  D. Mash,et al.  D3 Dopamine and Kappa Opioid Receptor Alterations in Human Brain of Cocaine‐overdose Victims , 1999, Annals of the New York Academy of Sciences.

[65]  D. Mash,et al.  Up-regulation of D3 dopamine receptor mRNA in the nucleus accumbens of human cocaine fatalities. , 1997, Brain research. Molecular brain research.

[66]  S. J. Gatley,et al.  Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects , 1997, Nature.

[67]  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.

[68]  P. Södersten,et al.  Altered dopamine function in pathological gambling , 1997, Psychological Medicine.

[69]  N. Volkow,et al.  Dopamine D2 Receptor Availability in Opiate-Dependent Subjects before and after Naloxone-Precipitated Withdrawal , 1997, Neuropsychopharmacology.

[70]  G. Logan,et al.  Impulsivity and Inhibitory Control , 1997 .

[71]  A. Lammertsma,et al.  Simplified Reference Tissue Model for PET Receptor Studies , 1996, NeuroImage.

[72]  D. Mash,et al.  Adaptive Increase in D3 Dopamine Receptors in the Brain Reward Circuits of Human Cocaine Fatalities , 1996, The Journal of Neuroscience.

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

[74]  M. Sanchez-Craig,et al.  Empirically based guidelines for moderate drinking: 1-year results from three studies with problem drinkers. , 1995, American journal of public health.

[75]  G. Chiara.  The role of dopamine in drug abuse viewed from the perspective of its role in motivation , 1995 .

[76]  J. Joyce,et al.  Localization of dopamine D3 receptors to mesolimbic and D2 receptors to mesostriatal regions of human forebrain. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[77]  R. Foltin,et al.  Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. , 1991, British journal of addiction.

[78]  L. Kozlowski,et al.  The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. , 1991, British journal of addiction.

[79]  H. Skinner,et al.  Diagnostic validity of the MAST and the alcohol dependence scale in the assessment of DSM-III alcohol disorders. , 1990, Journal of studies on alcohol.

[80]  Bruno Giros,et al.  Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics , 1990, Nature.

[81]  N. Volkow,et al.  Effects of chronic cocaine abuse on postsynaptic dopamine receptors. , 1990, The American journal of psychiatry.

[82]  M. Linnoila,et al.  Cerebrospinal fluid monoamine metabolites and suicidal behavior in depressed patients. A 5-year follow-up study. , 1989, Archives of general psychiatry.

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

[84]  H. Lesieur,et al.  Pathological gambling among high school students. , 1987, Addictive behaviors.

[85]  S. Shacham,et al.  A shortened version of the Profile of Mood States. , 1983, Journal of personality assessment.

[86]  H. Skinner,et al.  The drug abuse screening test. , 2013, Addictive behaviors.

[87]  H A Skinner,et al.  Alcohol dependence syndrome: measurement and validation. , 1982, Journal of abnormal psychology.

[88]  A. Beck,et al.  Screening depressed patients in family practice. A rapid technic. , 1972, Postgraduate medicine.

[89]  M. Hamilton.  A RATING SCALE FOR DEPRESSION , 1960, Journal of neurology, neurosurgery, and psychiatry.